Pyrrolopyridines as kinase inhibitors

ABSTRACT

Compounds of Formula I are useful for inhibition of CHK1 and/or CHK2. Methods of using compounds of Formula I and stereoisomers and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

PRIORITY OF INVENTION

This application is a continuation of U.S. patent application Ser. No.14/591,691, filed on Jan. 7, 2015, which is a continuation of U.S.patent application Ser. No. 14/271,129, filed on May 6, 2014, which hasissued as U.S. Pat. No. 8,981,085 which is a continuation of U.S. patentapplication Ser. No. 13/974,895, filed Aug. 23, 2013, which has issuedas U.S. Pat. No. 8,758,830, which is a continuation of U.S. patentapplication Ser. No. 13/425,186, filed Mar. 20, 2012, which has issuedas U.S. Pat. No. 8,545,897, which is a divisional of U.S. patentapplication Ser. No. 12/992,468, filed Nov. 12, 2010, which has issuedas U.S. Pat. No. 8,178,131, which is a 35 U.S.C. 371 national stageapplication of International Patent Application No. PCT/US2009/043691,filed May 13, 2009, and claims priority to U.S. Provisional ApplicationNo. 61/052,926 that was filed on May 13, 2008, which are incorporatedherein by reference in their entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to novel compounds, to pharmaceuticalcompositions comprising the compounds, to a process for making thecompounds and to the use of the compounds in therapy. More particularlyit relates to certain substituted pyrrolo[2,3-b]pyridines useful in thetreatment and prevention of hyperproliferative diseases.

Description of the State of the Art

Protein kinases are kinase enzymes that phosphorylate other proteins.The phosphorylation of these proteins usually produces a functionalchange in the protein. Most kinases act on serine and threonine ortyrosine, and some kinases act on all three. Through these functionalchanges, kinases can regulate many cellular pathways. Protein kinaseinhibitors are compounds that inhibit these protein kinases, and thuscan be used to affect cellular pathways.

Checkpoint kinase 1 (“CHK1”) is a serine/threonine kinase. CHK1regulates cell-cycle progression and is a main factor in DNA-damageresponse within a cell. CHK1 inhibitors have been shown to sensitizetumor cells to a variety of genotoxic agents, such as chemotherapy andradiation. (Tse, Archie N., et al., “Targeting Checkpoint Kinase 1 inCancer Therapeutics.” Clin. Cancer Res. 13(7) (2007) 1955-1960). It hasbeen observed that many tumors are deficient in the G₁ DNA damagecheckpoint pathway, resulting in the reliance on S and G₂ checkpoints torepair DNA damage and survive. (Janetka, James W., et al., “Inhibitorsof checkpoint kinases: From discovery to the clinic.” Drug Discovery &Development Vol. 10, No. 4 (2007) 473-486). The S and G₂ checkpoints areregulated by CHK1. Inhibition of CHK1 has been shown to cancel the S andG₂ checkpoints, thereby impairing DNA repair and resulting in increasedtumor cell death. However, non-cancerous cells have a functioning G₁checkpoint, allowing for DNA repair and survival.

Checkpoint kinase 2 (“CHK2”) is also a serine/threonine kinase. CHK2'sfunctions are central to the induction of cell cycle arrest andapoptosis by DNA damage. (Ahn, Jinwoo, et al., “The Chk2 proteinkinase.” DNA Repair 3 (2004) 1039-1047). CHK2 is activated in responseto genotoxic insults and propagates the checkpoint signal along severalpathways, which eventually causes cell-cycle arrest in the G₁, S andG₂/M phases, activation of DNA repair, and apoptotic cell death.(Bartek, Jiri, et al., “CHK2 Kinase—A Busy Messenger.” Nature ReviewsMolecular Cell Biology. Vol. 2(12) (2001) 877-886). Cancer cells oftenlack one or more genome-integrity checkpoints, so inhibition of CHK2could make tumor cells selectively more sensitive to anti-cancertherapies, such as γ-radiation or DNA-damaging drugs. Normal cells wouldstill activate other checkpoints and recover, while cancer cellsdeprived of checkpoints would be more likely to die. It has beendemonstrated that a peptide-based inhibitor of CHK2 abrogated the G₂checkpoint and sensitized p53-defective cancer cells to DNA damagingagents. (Pommier, Yves, et al., “Targeting Chk2 Kinase: MolecularInteraction Maps and Therapeutic Rationale.” Current PharmaceuticalDesign. Vol. 11, No. 22 (2005) 2855-2872).

CHK1 and/or CHK2 inhibitors are known, see for example, InternationalPublication WO 2009/004329, International Publication WO 2008/075007,International Publication WO 2007/090493, International Publication WO2007/090494, International Publication WO 2006/106326, InternationalPublication WO 2006/120573, International Publication WO 2005/103036 andInternational Publication WO 03/028724.

Kinase inhibitors are known, see for example, International PublicationWO 2008/106692, International Publication WO 2008/012635, InternationalPublication WO 2006/046023, International Publication WO 2006/127587,International Publication WO 2007/070514, International Publication WO2007/084667, International Publication WO 2007/125310, InternationalPublication WO 2007/125315 and International Publication WO 2007/125321.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to compounds that areinhibitors of CHK1 and/or CHK2. Accordingly, the compounds of thepresent invention are useful in the treatment of diseases and conditionsthat can be treated by the inhibition of CHK1 and/or CHK2 proteinkinases.

More specifically, one aspect of the present invention providescompounds of Formula I:

and stereoisomers, tautomers and pharmaceutically acceptable saltsthereof, wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(6a), R⁷, A and p are asdefined herein.

Another aspect of the present invention provides methods of preventingor treating a disease or disorder modulated by CHK1 and/or CHK2,comprising administering to a mammal in need of such treatment aneffective amount of a compound of this invention or a stereoisomer orpharmaceutically acceptable salt thereof. Examples of such diseases anddisorders include, but are not limited to, hyperproliferative disorders(such as cancer), neurodegeneration, cardiac hypertrophy, pain,migraine, and neurotraumatic disease.

Another aspect of the present invention provides methods of preventingor treating cancer, comprising administering to a mammal in need of suchtreatment an effective amount of a compound of this invention, or astereoisomer or pharmaceutically acceptable salt thereof, alone or incombination with one or more additional compounds having anti-cancerproperties.

Another aspect of the present invention provides a method of treating ahyperproliferative disease in a mammal comprising administering atherapeutically effective amount of a compound of this invention to themammal.

Another aspect of the present invention provides the compounds of thisinvention for use in therapy.

Another aspect of the present invention provides the compounds of thisinvention for the use in the treatment of a hyperproliferative disease.

Another aspect of the present invention provides the use of a compoundof this invention in the manufacture of a medicament for the treatmentof a hyperproliferative disease. In a further embodiment, thehyperproliferative disease is cancer.

Another aspect of the present invention provides the use of a compoundof the present invention in the manufacture of a medicament, for use asa CHK1 and/or CHK2 inhibitor in the treatment of a patient undergoingcancer therapy.

Another aspect of the present invention provides the use of a compoundof the present invention in the treatment of a hyperproliferativedisease. In a further aspect, the hyperproliferative disease is cancer.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention for use inthe treatment of a hyperproliferative disease.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention for use inthe treatment of cancer.

Another aspect of the present invention provides a pharmaceuticalcomposition comprising a compound of this invention or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.

Another aspect of the present invention provides intermediates forpreparing compounds of Formula I. Certain compounds of Formula I may beused as intermediates for other compounds of Formula I.

Another aspect of the present invention includes methods of preparing,methods of separation, and methods of purification of the compounds ofthis invention.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents, which may be included within the scopeof the present invention as defined by the claims. One skilled in theart will recognize many methods and materials similar or equivalent tothose described herein, which could be used in the practice of thepresent invention. The present invention is in no way limited to themethods and materials described. In the event that one or more of theincorporated literature and similar materials differs from orcontradicts this application, including but not limited to definedterms, term usage, described techniques, or the like, this applicationcontrols.

DEFINITIONS

The term “alkyl” includes linear or branched-chain radicals of carbonatoms. Some alkyl moieties have been abbreviated, for example, methyl(“Me”), ethyl (“Et”), propyl (“Pr”) and butyl (“Bu”), and furtherabbreviations are used to designate specific isomers of compounds, forexample, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”),1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”),1-methylpropyl or s-butyl (“s-Bu”), 1,1-dimethylethyl or t-butyl(“t-Bu”) and the like. The abbreviations are sometimes used inconjunction with elemental abbreviations and chemical structures, forexample, methanol (“MeOH”) or ethanol (“EtOH”).

Additional abbreviations that may be used throughout the applicationinclude, for example, benzyl (“Bn”), phenyl (“Ph”) and acetate (“Ac”).

The terms “heterocycle” and “heterocyclic” include four to sevenmembered rings containing one, two or three heteroatoms selected fromthe group consisting of oxygen, nitrogen and sulfur. In certaininstances, these terms may be specifically further limited, such as,“five to six membered heterocyclic” only including five and six memberedrings. Exemplary heterocyclic groups include, but are not limited to,oxiranyl, thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl,1,2-dithietanyl, 1,3-dithietanyl, tetrahydrofuranyl,tetrahydrothiophenyl, dithiolanyl, pyrrolidinyl, pyrazolidinyl,imidazolidinyl, 1,3-dioxolanyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl, 1,4-oxathianyl,morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl, thioxanyl,oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl,1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thieazepanyl, and 1,4-diazepanyl.

Exemplary partially unsaturated heterocyclic groups include, but are notlimited to, tetrahydropyridinyl, dihydropyridinyl, dihydropyranyl,dihydrofuranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H-pyranyl,4H-pyranyl, and pyrazolinyl.

The term “heteroaryl” includes five to six membered aromatic ringscontaining one, two or three heteroatoms selected from the groupconsisting of oxygen, nitrogen and sulfur. In certain instances, theseterms may be specifically further limited, such as, five to six memberedheteroaryl, wherein the heteroaryl contains one or two nitrogenheteroatoms. Exemplary heteroaryl groups include, but are not limitedto, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl,1-oxa-2,3-diazolyl, I-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl,1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl,1-thia-2,5-diazolyl, l-thia-3,4-diazolyl, tetrazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, furazanyl, and triazinyl.

The term “C₂-C₆ alkanoylalkyl” as used herein, represents an alkanoylgroup attached through an alkyl group (i.e.,(alkanoyl)-(alkyl)-compound), wherein the alkanoyl and alkyl groups havea combined two to six carbon atoms. Exemplary C₂-C₆ alkanoylalkyl groupsinclude ethanoylmethyl, ethanoylethyl, ethanoylpropyl, ethanoylbutyl,propanoylmethyl, propanoylethyl, propanoylpropyl, butanoylmethyl,butanoylethyl, and pentanoylmethyl.

The terms “treat” or “treatment” refer to therapeutic, prophylactic,palliative or preventative measures. For purposes of this invention,beneficial or desired clinical results include, but are not limited to,alleviation of symptoms, diminishment of extent of disease, stabilized(i.e., not worsening) state of disease, delay or slowing of diseaseprogression, amelioration or palliation of the disease state, andremission (whether partial or total), whether detectable orundetectable. “Treatment” can also mean prolonging survival as comparedto expected survival if not receiving treatment. Those in need oftreatment include those already with the condition or disorder, as wellas those prone to have the condition or disorder or those in which thecondition or disorder is to be prevented.

The phrases “therapeutically effective amount” or “effective amount”mean an amount of a compound of the present invention that, whenadministered to a mammal in need of such treatment, sufficient to (i)treat or prevent the particular disease, condition, or disorder, (ii)attenuate, ameliorate, or eliminate one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevent or delaythe onset of one or more symptoms of the particular disease, condition,or disorder described herein. The amount of a compound that willcorrespond to such an amount will vary depending upon factors such asthe particular compound, disease condition and its severity, theidentity (e.g., weight) of the mammal in need of treatment, but cannevertheless be routinely determined by one skilled in the art.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byabnormal or unregulated cell growth. A “tumor” comprises one or morecancerous cells. Examples of cancer include, but are not limited to,carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoidmalignancies. More particular examples of such cancers include squamouscell cancer (e.g., epithelial squamous cell cancer), lung cancer(including small-cell lung cancer, non-small cell lung cancer (“NSCLC”),adenocarcinoma of the lung and squamous carcinoma of the lung), cancerof the peritoneum, hepatocellular cancer, gastric or stomach cancerincluding gastrointestinal cancer, pancreatic cancer, glioblastoma,cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma,breast cancer, colon cancer, rectal cancer, colorectal cancer,endometrial or uterine carcinoma, salivary gland carcinoma, kidney orrenal cancer, prostate cancer, vulval cancer, thyroid cancer, hepaticcarcinoma, anal carcinoma, penile carcinoma, skin cancer, includingmelanoma, as well as head and neck cancer.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically, with theother ingredients comprising a formulation, and/or the mammal beingtreated therewith.

The phrase “pharmaceutically acceptable salt,” as used herein, refers topharmaceutically acceptable organic or inorganic salts of a compound ofthe invention.

The compounds of this invention also include other salts of suchcompounds which are not necessarily pharmaceutically acceptable salts,and which may be useful as intermediates for preparing and/or purifyingcompounds of this invention and/or for separating enantiomers ofcompounds of this invention.

The term “mammal” means a warm-blooded animal that has or is at risk ofdeveloping a disease described herein and includes, but is not limitedto, guinea pigs, dogs, cats, rats, mice, hamsters, and primates,including humans.

CHK1/2 Inhibitors

The present invention provides certain substitutedpyrrolo[2,3-b]pyridines, and pharmaceutical formulations thereof, thatinhibit CHK1 and/or CHK2. These compounds are potentially useful in thetreatment of diseases, conditions and/or disorders modulated by CHK1and/or CHK2.

One embodiment of this invention provides compounds of Formula I:

and stereoisomers, tautomers and pharmaceutically acceptable saltsthereof, wherein:

A is selected from a direct bond or CR^(a)R^(b);

R¹ is selected from hydrogen, halogen, CN, C₁-C₆ alkyl, C₁-C₆ alkenyl,—O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), C₃-C₆ cycloalkyl, a 4 to 6 memberedheterocyclic, phenyl, and a 5 or 6 membered heteroaryl, wherein thealkyls, alkenyl, cycloalkyl, heterocyclic, phenyl or heteroaryl areoptionally substituted with one or more groups selected from halogen,CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d);

R² is selected from C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), asaturated or partially unsaturated C₃-C₆ cycloalkyl, phenyl, a saturatedor partially unsaturated 4 to 6 membered heterocyclic, a 5 or 6 memberedheteroaryl, an 8 to 10 membered bicyclic aryl, an 8 to 10 memberedbicyclic heterocyclic, and an 8 to 10 membered bicyclic heteroaryl,wherein the alkyls, cycloalkyl, phenyl, heterocyclics, heteroaryls andaryl are optionally substituted with one or more groups selected fromOH, CN, halogen, oxo (except not on phenyl, aryl or heteroaryl), CF₃,cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl),—S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl, wherein the phenyl isoptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h);

R³ and R⁴ are independently selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F, —O(C₁-C₃ alkyl) or C₃-C₆ cycloalkyl,or

R³ and R⁴ together with the atoms to which they are attached form a 5 or6 membered ring;

R⁵ is selected from hydrogen and CH₃, or

A is CR^(a)R^(b), R^(a) and R^(b) are hydrogen, and R³ and R⁵ togetherwith the atoms to which they are attached form a 5 or 6 membered ring;

R⁶ is selected from hydrogen, F, OH, —OCH₃, C₁-C₃ alkyl and cyclopropyl,or

A is a direct bond, R^(6a) is hydrogen and R³ and R⁶ together with theatoms to which they are attached form a 5 or 6 membered ring;

R^(6a) is selected from hydrogen, F, OH and CH₃;

R⁷ is hydrogen, or

A is CR^(a)R^(b) and R³ and R⁷ together with the atoms to which they areattached form a 5 or 6 membered ring;

R^(a) is hydrogen, or

R⁴ and R^(b) are absent and R³ and R^(a) together with the atoms towhich they are attached form an aromatic 5 or 6 membered ring;

R^(b) is hydrogen or absent;

R^(c) and R^(d) are independently selected from hydrogen and C₁-C₃alkyl, or

R^(c) and R^(d) together with the atom to which they are attached form a5 or 6 membered ring;

R^(e) and R^(f) are independently selected from hydrogen and C₁-C₃alkyl;

R^(g) and R^(h) are independently selected from hydrogen and C₁-C₃alkyl;

R^(i) is C₁-C₃ alkyl; and

p is 0, 1, 2 or 3.

Compounds of Formula I include compounds wherein:

A is selected from a direct bond or CR^(a)R^(b);

R¹ is selected from halogen, CN, C₁-C₆ alkyl, C₁-C₆ alkenyl, —O(C₁-C₆alkyl), —S(C₁-C₆ alkyl), C₃-C₆ cycloalkyl, a 4 to 6 memberedheterocyclic, phenyl, and a 5 or 6 membered heteroaryl, wherein thealkyls, alkenyl, cycloalkyl, heterocyclic, phenyl or heteroaryl areoptionally substituted with one or more groups selected from halogen,CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d);

R² is selected from C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), asaturated or partially unsaturated C₃-C₆ cycloalkyl, phenyl, a saturatedor partially unsaturated 4 to 6 membered heterocyclic, a 5 or 6 memberedheteroaryl, an 8 to 10 membered bicyclic aryl, an 8 to 10 memberedbicyclic heterocyclic, and an 8 to 10 membered bicyclic heteroaryl,wherein the alkyls, cycloalkyl, phenyl, heterocyclics, heteroaryls andaryl are optionally substituted with one or more groups selected fromOH, CN, halogen, oxo (except not on phenyl, aryl or heteroaryl), CF₃,cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl),—S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl, wherein the phenyl isoptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h);

R³ and R⁴ are independently selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F, —O(C₁-C₃ alkyl) or C₃-C₆ cycloalkyl,or

R³ and R⁴ together with the atoms to which they are attached form a 5 or6 membered ring;

R⁵ is selected from hydrogen and CH₃, or

A is CR^(a)R^(b), R^(a) and R^(b) are hydrogen, and R³ and R⁵ togetherwith the atoms to which they are attached form a 5 or 6 membered ring;

R⁶ is selected from hydrogen, F, OH, —OCH₃, C₁-C₃ alkyl and cyclopropyl,or

A is a direct bond, R^(6a) is hydrogen and R³ and R⁶ together with theatoms to which they are attached form a 5 or 6 membered ring;

R^(6a) is selected from hydrogen, F, OH and CH₃;

R⁷ is hydrogen, or

A is CR^(a)R^(b) and R³ and R⁷ together with the atoms to which they areattached form a 5 or 6 membered ring;

R^(a) is hydrogen, or

R⁴ and R^(b) are absent and R³ and R^(a) together with the atoms towhich they are attached form an aromatic 5 or 6 membered ring;

R^(b) is hydrogen or absent;

R^(c) and R^(d) are independently selected from hydrogen and C₁-C₃alkyl, or

R^(c) and R^(d) together with the atom to which they are attached form a5 or 6 membered ring;

R^(e) and R^(f) are independently selected from hydrogen and C₁-C₃alkyl;

R^(g) and R^(h) are independently selected from hydrogen and C₁-C₃alkyl;

R^(i) is C₁-C₃ alkyl; and

p is 0, 1, 2 or 3.

Compounds of Formula I include compounds wherein:

A is selected from a direct bond or CR^(a)R^(b);

R¹ is selected from hydrogen, halogen, CN, C₁-C₆ alkyl, C₁-C₆ alkenyl,—O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), C₃-C₆ cycloalkyl, phenyl, and a 5 or 6membered heteroaryl, wherein the alkyls, alkenyl, cycloalkyl, phenyl orheteroaryl are optionally substituted with one or more groups selectedfrom halogen, C₁-C₃ alkyl and —O(C₁-C₃ alkyl);

R² is selected from C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), asaturated C₃-C₆ cycloalkyl, phenyl, a saturated or partially unsaturated4 to 6 membered heterocycle, a 5 or 6 membered heteroaryl, and an 8 to10 membered bicyclic heteroaryl, wherein the alkyls, cycloalkyl, phenyl,heterocycle, and heteroaryls are optionally substituted with one or moregroups selected from OH, CN, halogen, oxo (except not on phenyl orheteroaryl), CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆alkyl, —O(C₁-C₆ alkyl), and phenyl;

R³ and R⁴ are independently selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F, —O(C₁-C₃ alkyl) or C₃-C₆ cycloalkyl;

R⁵ is selected from hydrogen and CH₃, or

A is CR^(a)R^(b), R^(a) and R^(b) are hydrogen, and R³ and R⁵ togetherwith the atoms to which they are attached form a 5 or 6 membered ring;

R⁶ is selected from hydrogen, F, —OCH₃, C₁-C₃ alkyl, and cyclopropyl, or

A is a direct bond, R^(6a) is hydrogen and R³ and R⁶ together with theatoms to which they are attached form a 5 or 6 membered ring;

R^(6a) is hydrogen;

R⁷ is hydrogen, or

A is CR^(a)R^(b) and R³ and R⁷ together with the atoms to which they areattached form a 5 or 6 membered ring;

R^(a) is hydrogen, or

R⁴ and R^(b) are absent and R³ and R^(a) together with the atoms towhich they are attached form an aromatic 5 or 6 membered ring;

R^(b) is hydrogen or absent;

R^(i) is C₁-C₃ alkyl; and

p is 0, 1, 2 or 3.

Compounds of Formula I include compounds wherein:

A is selected from a direct bond or CR^(a)R^(b);

R¹ is selected from halogen, CN, C₁-C₆ alkyl, C₁-C₆ alkenyl, —O(C₁-C₆alkyl), —S(C₁-C₆ alkyl), C₃-C₆ cycloalkyl, phenyl, and a 5 or 6 memberedheteroaryl, wherein the alkyls, alkenyl, cycloalkyl, phenyl orheteroaryl are optionally substituted with one or more groups selectedfrom halogen and C₁-C₃ alkyl;

R² is selected from C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), asaturated C₃-C₆ cycloalkyl, phenyl, a saturated or partially unsaturated4 to 6 membered heterocycle, a 5 or 6 membered heteroaryl, and an 8 to10 membered bicyclic heteroaryl, wherein the alkyls, cycloalkyl, phenyl,heterocycle, and heteroaryls are optionally substituted with one or moregroups selected from OH, CN, halogen, oxo (except not on phenyl orheteroaryl), CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆alkyl, —O(C₁-C₆ alkyl), and phenyl;

R³ and R⁴ are independently selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F, —O(C₁-C₃ alkyl) or C₁-C₆ cycloalkyl;

R⁵ is selected from hydrogen and CH₃, or

A is CR^(a)R^(b), R^(a) and R^(b) are hydrogen, and R³ and R⁵ togetherwith the atoms to which they are attached form a 5 or 6 membered ring;

R⁶ is selected from hydrogen, F, —OCH₃, C₁-C₃ alkyl, and cyclopropyl, or

A is a direct bond, R^(6a) is hydrogen and R³ and R⁶ together with theatoms to which they are attached form a 5 or 6 membered ring;

R^(6a) is hydrogen;

R⁷ is hydrogen, or

A is CR^(a)R^(b) and R³ and R⁷ together with the atoms to which they areattached form a 5 or 6 membered ring;

R^(a) is hydrogen, or

R⁴ and R^(b) are absent and R³ and R^(a) together with the atoms towhich they are attached form an aromatic 5 or 6 membered ring;

R^(b) is hydrogen or absent;

R^(i) is C₁-C₃ alkyl; and

p is 0, 1, 2 or 3.

Compounds of Formula I include compounds wherein:

A is selected from a direct bond or CR^(a)R^(b);

R¹ is selected from hydrogen, halogen, C₁-C₆ alkyl, —S(C₁-C₆ alkyl),C₃-C₆ cycloalkyl, a 5 or 6 membered heterocyclic, phenyl, and a 5 or 6membered heteroaryl, wherein the alkyls, cycloalkyl, heterocyclic,phenyl or heteroaryl are optionally substituted with one or more groupsselected from halogen, CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), andNR^(c)R^(d);

R² is selected from C₁-C₆ alkyl, a saturated or partially unsaturatedC₃-C₆ cycloalkyl, phenyl, a saturated or partially unsaturated 5 or 6membered heterocycle, a 5 or 6 membered heteroaryl, an 8 to 10 memberedbicyclic aryl, an 8 to 10 membered bicyclic heterocyclic, and an 8 to 10membered bicyclic heteroaryl, wherein the alkyl, cycloalkyl, phenyl,heterocyclics, heteroaryls and aryl are optionally substituted with oneor more groups selected from OH, CN, halogen, oxo (except not on phenyl,aryl or heteroaryl), CF₃, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl),and NR^(e)R^(f);

R³ and R⁴ are independently selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F or C₃-C₆ cycloalkyl, or

R³ and R⁴ together with the atoms to which they are attached form a 5 or6 membered ring;

R⁵ is selected from hydrogen and CH₃, or

A is CR^(a)R^(b), R^(a) and R^(b) are hydrogen, and R³ and R⁵ togetherwith the atoms to which they are attached form a 5 or 6 membered ring;

R⁶ is selected from hydrogen, F, OH, —OCH₃, and C₁-C₃ alkyl, or

A is a direct bond, R^(6a) is hydrogen and R³ and R⁶ together with theatoms to which they are attached form a 5 or 6 membered ring;

R^(6a) is selected from hydrogen, F, OH and —OCH₃;

R⁷ is hydrogen, or

A is CR^(a)R^(b) and R³ and R⁷ together with the atoms to which they areattached form a 5 or 6 membered ring;

R^(a) is hydrogen, or

R⁴ and R^(b) are absent and R³ and R^(a) together with the atoms towhich they are attached form an aromatic 5 or 6 membered ring;

R^(b) is hydrogen or absent;

R^(c) and R^(d) are independently selected from hydrogen and C₁-C₃alkyl, or

R^(c) and R^(d) together with the atom to which they are attached form a5 or 6 membered ring;

R^(e) and R^(f) are independently selected from hydrogen and C₁-C₃alkyl; and

p is 0, 1, 2 or 3.

Compounds of Formula I include compounds wherein:

A is selected from a direct bond or CR^(a)R^(b);

R¹ is selected from halogen, C₃-C₆ cycloalkyl and C₁-C₆ alkyl, whereinthe alkyl is optionally substituted with one or more halogen groups;

R² is selected from C₁-C₆ alkyl, saturated C₃-C₆ cycloalkyl, phenyl,saturated or partially unsaturated 5 or 6 membered heterocyclic, a 5 or6 membered heteroaryl, and an 8 to 10 membered bicyclic heteroaryl,wherein the alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryls areoptionally substituted with halogen, oxo (except not on phenyl orheteroaryl), CF₃, C₁-C₆ alkyl, —O(C₁-C₆ alkyl) or C₃-C₆ cycloalkyl;

R³ is selected from hydrogen or C₁-C₄ alkyl optionally substituted withOH or C₃-C₆ cycloalkyl;

R⁴ is selected from hydrogen and C₁-C₄ alkyl;

R⁵ is selected from hydrogen and CH₃, or

A is CR^(a)R^(b), R^(a) and R^(b) are hydrogen, and R³ and R⁵ togetherwith the atoms to which they are attached form a 5 or 6 membered ring;

R⁶ is hydrogen, or

A is a direct bond and R³ and R⁶ together with the atoms to which theyare attached form a 5 or 6 membered ring;

R^(6a) is hydrogen;

R⁷ is selected from hydrogen, or

A is CR^(a)R^(b) and R³ and R⁷ together with the atoms to which they areattached form a 5 or 6 membered ring;

R^(a) and R^(b) are hydrogen, or

R⁴ and R^(b) are absent and R³ and R^(a) together with the atoms towhich they are attached form an aromatic 5 or 6 membered ring; and

p is 0, 1, 2 or 3.

Compounds of Formula I include compounds wherein:

A is selected from a direct bond or CR^(a)R^(b);

R¹ is selected from halogen, C₃-C₆ cycloalkyl and C₁-C₆ alkyl, whereinthe alkyl is optionally substituted with one or more halogen groups;

R² is selected from C₁-C₆ alkyl, saturated C₃-C₆ cycloalkyl, phenyl,saturated or partially unsaturated 5 or 6 membered heterocyclic, a 5 or6 membered heteroaryl, and an 8 to 10 membered bicyclic heteroaryl,wherein the alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryls areoptionally substituted with halogen, oxo (except not on phenyl orheteroaryl), CF₃, C₁-C₆ alkyl, —O(C₁-C₆ alkyl) or C₃-C₆ cycloalkyl;

R³ is selected from hydrogen or C₁-C₄ alkyl optionally substituted withOH or C₃-C₆ cycloalkyl;

R⁴ is selected from hydrogen and C₁-C₄ alkyl;

R⁵ is selected from hydrogen and CH₃, or

A is CR^(a)R^(b), R^(a) and R^(b) are hydrogen, and R³ and R⁵ togetherwith the atoms to which they are attached form a 5 or 6 membered ring;

R⁶ is hydrogen, or

A is a direct bond and R³ and R⁶ together with the atoms to which theyare attached form a 5 or 6 membered ring;

R^(6a) is hydrogen;

R⁷ is selected from hydrogen, or

A is CR^(a)R^(b) and R³ and R⁷ together with the atoms to which they areattached form a 5 or 6 membered ring;

R^(a) and R^(b) are hydrogen, or

R⁴ and R^(b) are absent and R³ and R^(a) together with the atoms towhich they are attached form an aromatic 5 or 6 membered ring; and

p is 1 or 2.

In certain embodiments, p is 0, 1, 2 or 3.

In certain embodiments, p is 0, 1, or 2.

In certain embodiments, p is 1 or 2.

In certain embodiments, p is 0, as shown in Formula IIa:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(6a), R⁷ and A are as defined herein.

In certain embodiments, p is 1, as shown in Formula IIb:

wherein R¹, R², R³, R⁴, R⁵. R⁶, R^(6a), R⁷ and A are as defined herein.

In certain embodiments, p is 2, as shown in Formula IIc:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(6a), R⁷ and A are as defined herein.

In certain embodiments, p is 3, as shown in Formula IId:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(6a), R⁷ and A are as defined herein.

In certain embodiments, R¹ is selected from hydrogen, halogen, CN, C₁-C₆alkyl, C₁-C₆ alkenyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), C₃-C₆cycloalkyl, a 4 to 6 membered heterocyclic, phenyl, and a 5 or 6membered heteroaryl, wherein the alkyls, alkenyl, cycloalkyl,heterocyclic, phenyl or heteroaryl are optionally substituted with oneor more groups selected from halogen, CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃alkyl) and NR^(c)R^(d).

In certain embodiments, R¹ is selected from halogen, CN, C₁-C₆ alkyl,C₁-C₆ alkenyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), C₃-C₆ cycloalkyl, a 4to 6 membered heterocyclic, phenyl, and a 5 or 6 membered heteroaryl,wherein the alkyls, alkenyl, cycloalkyl, heterocyclic, phenyl orheteroaryl are optionally substituted with one or more groups selectedfrom halogen, CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d).

In certain embodiments, R¹ is selected from hydrogen, halogen, CN, C₁-C₆alkyl, C₁-C₆ alkenyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), C₃-C₆cycloalkyl, phenyl, and a 5 or 6 membered heteroaryl, wherein thealkyls, alkenyl, cycloalkyl, phenyl or heteroaryl are optionallysubstituted with one or more groups selected from halogen, C₁-C₃ alkyland —O(C₁-C₃ alkyl).

In certain embodiments, R¹ is selected from halogen, CN, C₁-C₆ alkyl,C₁-C₆ alkenyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), C₃-C₆ cycloalkyl,phenyl, and a 5 or 6 membered heteroaryl, wherein the alkyls, alkenyl,cycloalkyl, phenyl or heteroaryl are optionally substituted with one ormore groups selected from halogen, C₁-C₃ alkyl and —O(C₁-C₃ alkyl).

In certain embodiments, R¹ is selected from hydrogen, halogen, C₁-C₆alkyl, —S(C₁-C₆ alkyl), C₃-C₆ cycloalkyl, a 5 or 6 memberedheterocyclic, phenyl, and a 5 or 6 membered heteroaryl, wherein thealkyls, cycloalkyl, heterocyclic, phenyl or heteroaryl are optionallysubstituted with one or more groups selected from halogen, CN, CF₃,C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d).

In certain embodiments, R¹ is selected from halogen, C₃-C₆ cycloalkyland C₁-C₆ alkyl, wherein the alkyl is optionally substituted with one ormore halogen groups. In certain embodiments, R¹ is selected fromhalogen, C₃-C₆ cycloalkyl and C₁-C₆ alkyl, wherein the alkyl isoptionally substituted with one or more F groups.

In certain embodiments, R¹ is selected from hydrogen, Br, Cl, F, CN,CF₃, methyl, ethyl, isopropyl, prop-1-en-2-yl, —OCH₂CH₃, —OCH₂CH₂OCH₃,—SCH₃, —SCH₂CH₃, —SCH(CH₃)₂, cyclopropyl, phenyl and6-methylpyridin-3-yl.

In certain embodiments, R¹ is selected from Br, Cl, F, CN, CF₃, methyl,ethyl, isopropyl, prop-1-en-2-yl, —OCH₂CH₃, —OCH₂CH₂OCH₃, —SCH₃,—SCH₂CH₃, —SCH(CH₃)₂, cyclopropyl, phenyl and 6-methylpyridin-3-yl.

In certain embodiments, R¹ is selected from Br, Cl, F, cyclopropyl andCF₃.

In certain embodiments, R¹ is hydrogen.

In certain embodiments, R¹ is halogen. In certain embodiments, R¹ isselected from Br, Cl and F.

In certain embodiments, R¹ is CN.

In certain embodiments, R¹ is C₁-C₆ alkyl, wherein the alkyl isoptionally substituted with one or more groups selected from halogen,CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d). In certainembodiments, R¹ is C₁-C₆ alkyl. In certain embodiments, R¹ is methyl,ethyl or isopropyl.

In certain embodiments, R¹ is C₁-C₆ alkenyl, wherein the alkenyl isoptionally substituted with one or more groups selected from halogen,CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d). In certainembodiments, R¹ is C₁-C₆ alkenyl. In certain embodiments, R¹ isprop-1-en-2-yl.

In certain embodiments, R¹ is —O(C₁-C₆ alkyl), wherein the alkyl isoptionally substituted with one or more groups selected from halogen,CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d). In certainembodiments, R¹ is —O(C₁-C₆ alkyl) optionally substituted with —O(C₁-C₃alkyl). In certain embodiments, R¹ is —OCH₂CH₃ and —OCH₂CH₂OCH₃.

In certain embodiments, R¹ is —S(C₁-C₆ alkyl), wherein the alkyl isoptionally substituted with one or more groups selected from halogen,CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d). In certainembodiments, R¹ is —S(C₁-C₆ alkyl). In certain embodiments, R¹ is —SCH₃,—SCH₂CH₃ or —SCH(CH₃)₂.

In certain embodiments, R¹ is C₃-C₆ cycloalkyl optionally substitutedwith one or more groups selected from halogen, CN, CF₃, C₁-C₃ alkyl,—O(C₁-C₃ alkyl) and NR^(c)R^(d). In certain embodiments, R¹ is C₃-C₆cycloalkyl. In certain embodiments, R¹ is cyclopropyl.

In certain embodiments, R¹ is C₃-C₆ cycloalkyl. In certain embodiments,R¹ is cyclopropyl.

In certain embodiments, R¹ is C₁-C₆ alkyl, wherein the alkyl isoptionally substituted with one or more groups selected from halogen,CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d). In certainembodiments, R¹ is C₁-C₆ alkyl, wherein the alkyl is optionallysubstituted with one or more halogen groups. In certain embodiments, R¹is C₁-C₆ alkyl, wherein the alkyl is optionally substituted with three Fgroups. In certain embodiments, R¹ is CF₃.

In certain embodiments, R¹ is C₁-C₆ alkyl, wherein the alkyl isoptionally substituted with one or more halogen groups. In certainembodiments, R¹ is C₁-C₆ alkyl, wherein the alkyl is optionallysubstituted with three F groups. In certain embodiments, R¹ is CF₃.

In certain embodiments, R¹ is phenyl optionally substituted with one ormore groups selected from halogen, CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl)and NR^(c)R^(d). In certain embodiments, R¹ is phenyl.

In certain embodiments, R¹ is a 5 or 6 membered heteroaryl optionallysubstituted with one or more groups selected from halogen, CN, CF₃,C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d). In certain embodiments, R¹is a 5 or 6 membered heteroaryl optionally substituted with C₁-C₃ alkyl.In certain embodiments, R¹ is a 5 or 6 membered heteroaryl optionallysubstituted with C₁-C₃ alkyl, wherein the heteroaryl contains one or twoheteroatoms selected from nitrogen, oxygen and sulfur. In certainembodiments, R¹ is a 5 or 6 membered heteroaryl optionally substitutedwith C₁-C₃ alkyl, wherein the heteroaryl contains one or two nitrogenheteroatoms. In certain embodiments, R¹ is a 5 or 6 membered heteroaryloptionally substituted with C₁-C₃ alkyl, wherein the heteroaryl ispyridinyl. In certain embodiments, R¹ is 6-methylpyridin-3-yl.

In certain embodiments, R² is selected from C₁-C₆ alkyl, —O(C₁-C₆alkyl), —NH(C₁-C₆ alkyl), a saturated or partially unsaturated C₃-C₆cycloalkyl, phenyl, a saturated or partially unsaturated 4 to 6 memberedheterocyclic, a 5 or 6 membered heteroaryl, an 8 to 10 membered bicyclicaryl, an 8 to 10 membered bicyclic heterocyclic, and an 8 to 10 memberedbicyclic heteroaryl, wherein the alkyls, cycloalkyl, phenyl,heterocyclics, heteroaryls and aryl are optionally substituted with oneor more groups selected from OH, CN, halogen, oxo (except not on phenyl,aryl or heteroaryl), CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i),C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f) and phenyl,wherein the phenyl is optionally substituted with one or more groupsselected from OH, CN, halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), andNR^(h)R^(h).

In certain embodiments, R² is selected from C₁-C₆ alkyl, —O(C₁-C₆alkyl), —NH(C₁-C₆ alkyl), a saturated or partially unsaturated C₃-C₆cycloalkyl, phenyl, a saturated or partially unsaturated 4 to 6 memberedheterocyclic, a 5 or 6 membered heteroaryl, an 8 to 10 membered bicyclicaryl, an 8 to 10 membered bicyclic heterocyclic, and an 8 to 10 memberedbicyclic heteroaryl, wherein the alkyls, cycloalkyl, phenyl,heterocyclics, heteroaryls and aryl are optionally substituted with oneor more groups selected from OH, CN, halogen, oxo (except not on phenyl,aryl or heteroaryl), CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i),C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl.

In certain embodiments, R² is selected from C₁-C₆ alkyl, —O(C₁-C₆alkyl), —NH(C₁-C₆ alkyl), a saturated C₃-C₆ cycloalkyl, phenyl, asaturated or partially unsaturated 4 to 6 membered heterocyclic, a 5 or6 membered heteroaryl, and an 8 to 10 membered bicyclic heteroaryl,wherein the alkyls, cycloalkyl, phenyl, heterocyclic, and heteroarylsare optionally substituted with one or more groups selected from OH, CN,halogen, oxo (except not on phenyl, aryl or heteroaryl), CF₃,cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl),and phenyl.

In certain embodiments, R² is selected from C₁-C₆ alkyl, —O(C₁-C₆alkyl), —NH(C₁-C₆ alkyl), a saturated or partially unsaturated C₃-C₆cycloalkyl, phenyl, a saturated or partially unsaturated 4 to 6 memberedheterocyclic, a 5 or 6 membered heteroaryl, an 8 to 10 membered bicyclicaryl, an 8 to 10 membered bicyclic heterocyclic, and an 8 to 10 memberedbicyclic heteroaryl, wherein: (1) the alkyls, cycloalkyl, andheterocyclics are optionally substituted with one or more groupsselected from OH, CN, halogen, oxo, CF₃, cyclopropyl, cyclopropylmethyl,—SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f),and phenyl, wherein the phenyl is optionally substituted with one ormore groups selected from OH, CN, halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃alkyl), and NR^(g)R^(h); and (2) the phenyl, heteroaryls and aryl areoptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl,—O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl, wherein thephenyl is optionally substituted with one or more groups selected fromOH, CN, halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h).

In certain embodiments, R² is selected from C₁-C₆ alkyl, —O(C₁-C₆alkyl), —NH(C₁-C₆ alkyl), a saturated or partially unsaturated C₃-C₆cycloalkyl, phenyl, a saturated or partially unsaturated 4 to 6 memberedheterocyclic, a 5 or 6 membered heteroaryl, an 8 to 10 membered bicyclicaryl, an 8 to 10 membered bicyclic heterocyclic, and an 8 to 10 memberedbicyclic heteroaryl, wherein: (1) the alkyls, cycloalkyl, andheterocyclics are optionally substituted with one or more groupsselected from OH, CN, halogen, oxo, CF₃, cyclopropyl, cyclopropylmethyl,—SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f),and phenyl; and (2) the phenyl, heteroaryls and aryl are optionallysubstituted with one or more groups selected from OH, CN, halogen, CF₃,cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl),—S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl.

In certain embodiments, R² is selected from C₁-C₆ alkyl, —O(C₁-C₆alkyl), —NH(C₁-C₆ alkyl), a saturated C₃-C₆ cycloalkyl, phenyl, asaturated or partially unsaturated 4 to 6 membered heterocyclic, a 5 or6 membered heteroaryl, and an 8 to 10 membered bicyclic heteroaryl,wherein: (1) the alkyls, cycloalkyl, and heterocyclic are optionallysubstituted with one or more groups selected from OH, CN, halogen, oxo,CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆alkyl), and phenyl; and (2) the phenyl and heteroaryls are optionallysubstituted with one or more groups selected from OH, CN, halogen, CF₃,cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl),and phenyl.

In certain embodiments, R² is selected from C₁-C₆ alkyl, a saturated orpartially unsaturated C₃-C₆ cycloalkyl, phenyl, a saturated or partiallyunsaturated 5 or 6 membered heterocyclic, a 5 or 6 membered heteroaryl,an 8 to 10 membered bicyclic aryl, an 8 to 10 membered bicyclicheterocyclic, and an 8 to 10 membered bicyclic heteroaryl, wherein thealkyl, cycloalkyl, phenyl, heterocyclics, heteroaryls and aryl areoptionally substituted with one or more groups selected from OH, CN,halogen, oxo (except not on phenyl, aryl or heteroaryl), CF₃, C₁-C₆alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), and NR^(e)R^(f).

In certain embodiments, R² is selected from C₁-C₆ alkyl, a saturated orpartially unsaturated C₃-C₆ cycloalkyl, phenyl, a saturated or partiallyunsaturated 5 or 6 membered heterocyclic, a 5 or 6 membered heteroaryl,and an 8 to 10 membered bicyclic heteroaryl, wherein the alkyl,cycloalkyl, phenyl, heterocyclic and heteroaryls are optionallysubstituted with halogen, oxo (except not on phenyl or heteroaryl), CF₃,C₁-C₆ alkyl, —O(C₁-C₆ alkyl), or C₃-C₆ cycloalkyl. In certainembodiments, R² is selected from C₁-C₆ alkyl, a saturated C₃-C₆cycloalkyl, phenyl, a saturated or partially unsaturated 5 or 6 memberedheterocyclic, a 5 or 6 membered heteroaryl, and an 8 to 10 memberedbicyclic heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic areoptionally substituted with halogen, oxo, CF₃, C₁-C₆ alkyl, —O(C₁-C₆alkyl), or C₃-C₆ cycloalkyl, and wherein the phenyl and heteroaryls areoptionally substituted with halogen, CF₃, C₁-C₆ alkyl, —O(C₁-C₃ alkyl),or C₃-C₆ cycloalkyl.

In certain embodiments, R² is selected from methyl, ethyl, propyl,isopropyl, tert-butyl, isobutyl, cyclopropylmethyl, —CH₂CF₃,—CH(CH₂CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH(CH₃)OCH₃, —CH₂CH₂OCH₃,—CH(CH₃)OH, —C(CH₃)₂OH, —CH₂CN, —CH₂CH₂F, —C(CH₃)₂F, —CH(CH₃)CH₂CH₃,—CH₂OCH(CH₃)₂, —CH(CH₃)OCH(CH₃)₂, —CH₂SO₂CH₃, —CH(CH₃)phenyl,—CH₂(phenyl), —OCH₂CH₃, —NH(CH₂CH₃), cyclopropyl, cyclobutyl,cyclopentyl, 1-(trifluoromethyl)cyclopropyl, 1-(methoxy)cyclopropyl,2,2-difluorocyclopropyl, 1-methylcyclopropyl, 2-phenylcyclopropyl,2,2-dimethylcyclopropyl, phenyl, 3-methylphenyl, 4-fluorophenyl,3-methoxyphenyl, 3-fluorophenyl, 3-chloro-4-fluorophenyl,3-fluoro-4-methoxyphenyl, 3-trifluoromethylphenyl,2-fluoro-5-methylphenyl, 3-methyloxetan-3-yl, azetidin-1-yl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,I-methyl-6-oxo-1,6-dihydropyridin-3-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl,1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl,1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridazin-3-yl, morpholin-2-yl,pyrrolidin-1-yl, 5-oxopyrrolidin-2-yl, pyrazol-4-yl,1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 2-methyloxazol-4-yl,5-methylisoxazol-3-yl, 2-methylthiazol-4-yl, pyridin-2-yl, pyridin-3-yl,6-methoxy-pyridin-2-yl, 3-methylpyridin-2-yl, 5-chloro-pyridin-2-yl,5-trifluoromethylpyridin-2-yl, 2-methylpyridin-3-yl,5-methylpyridin-3-yl, 5-chloropyridin-3-yl, 6-methylpyridin-3-yl,pyrimidin-2-yl, 5-ethylpyrimidin-2-yl, pyrazin-2-yl,5-methylpyrazin-2-yl, and quinoxalin-2-yl.

In certain embodiments, R² is selected from isopropyl, tert-butyl,isobutyl, cyclopropylmethyl, —CH(CH₂CH₃)₂, —CH₂OCH₃, —CH(CH₃)OCH₃,—CH₂CH₂OCH₃, —CH(cyclopropyl)CF₃, cyclopropyl, cyclobutyl, cyclopentyl,phenyl, 3-methylphenyl, 4-fluorophenyl, 3-methoxyphenyl, 3-fluorophenyl,3-chloro-4-fluorophenyl, 3-fluoro-4-methoxyphenyl,3-trifluoromethylphenyl, 2-fluoro-5-methylphenyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, morpholin-2-yl, pyrazol-4-yl,1-methyl-1H-pyrazol-3-yl, 2-methyloxazol-4-yl, 5-methylisoxazol-3-yl,2-methylthiazol-4-yl, pyridin-2-yl, pyridin-3-yl,6-methoxy-pyridin-2-yl, 3-methylpyridin-2-yl, 5-chloro-pyridin-2-yl,5-methylpyridin-2-yl, 2-methylpyridin-3-yl, 5-methylpyridin-3-yl,5-chloropyridin-3-yl, 6-methylpyridin-3-yl, pyrimidin-2-yl,pyrazin-2-yl, 5-methylpyrazin-2-yl and quinoxalin-2-yl.

In the present invention, R² may be C₁-C₆ alkyl optionally substitutedwith oxo. As the R² substituent is immediately adjacent to the carbonylgroup of the amide at the 3 position of the 1H-pyrrolo[2,3-b]pyridine ofFormula I, when R² is C₁-C₆ alkyl optionally substituted with oxo thenthe first carbon (immediately adjacent to the carbonyl group of theamide) may not be substituted with an oxo group.

In certain embodiments, R² is selected from C₁-C₆ alkyl, —O(C₁-C₆alkyl), —NH(C₁-C₆ alkyl), C₂-C₆ alkanoylalkyl, a saturated or partiallyunsaturated C₃-C₆ cycloalkyl, phenyl, a saturated or partiallyunsaturated 4 to 6 membered heterocyclic, a 5 or 6 membered heteroaryl,an 8 to 10 membered bicyclic aryl, an 8 to 10 membered bicyclicheterocyclic, and an 8 to 10 membered bicyclic heteroaryl, wherein thealkyls, alkanoyl, cycloalkyl, phenyl, heterocyclics, heteroaryls andaryl are optionally substituted with one or more groups selected fromOH, CN, halogen, oxo (except not on alkyl, phenyl, aryl or heteroaryl),CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl, wherein the phenyl isoptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h).

In certain embodiments, R² is selected from C₁-C₆ alkyl, —O(C₁-C₆alkyl), —NH(C₁-C₆ alkyl), C₂-C₆ alkanoylalkyl, a saturated or partiallyunsaturated C₃-C₆ cycloalkyl, phenyl, a saturated or partiallyunsaturated 4 to 6 membered heterocyclic, a 5 or 6 membered heteroaryl,an 8 to 10 membered bicyclic aryl, an 8 to 10 membered bicyclicheterocyclic, and an 8 to 10 membered bicyclic heteroaryl, wherein thealkyls, alkanoyl, cycloalkyl, phenyl, heterocyclics, heteroaryls andaryl are optionally substituted with one or more groups selected fromOH, CN, halogen, oxo (except not on alkyl, phenyl, aryl or heteroaryl),CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl.

In certain embodiments, R² is selected from C₁-C₆ alkyl, —O(C₁-C₆alkyl), —NH(C₁-C₆ alkyl), C₂-C₆ alkanoylalkyl, a saturated C₃-C₆cycloalkyl, phenyl, a saturated or partially unsaturated 4 to 6 memberedheterocyclic, a 5 or 6 membered heteroaryl, and an 8 to 10 memberedbicyclic heteroaryl, wherein the alkyls, alkanoyl, cycloalkyl, phenyl,heterocyclic, and heteroaryls are optionally substituted with one ormore groups selected from OH, CN, halogen, oxo (except not on alkyl,phenyl, aryl or heteroaryl), CF₃, cyclopropyl, cyclopropylmethyl,—SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), and phenyl.

In certain embodiments, R² is selected from C₁-C₆ alkyl, —O(C₁-C₆alkyl), —NH(C₁-C₆ alkyl), C₂-C₆ alkanoylalkyl, a saturated or partiallyunsaturated C₃-C₆ cycloalkyl, phenyl, a saturated or partiallyunsaturated 4 to 6 membered heterocyclic, a 5 or 6 membered heteroaryl,an 8 to 10 membered bicyclic aryl, an 8 to 10 membered bicyclicheterocyclic, and an 8 to 10 membered bicyclic heteroaryl, wherein: (1)the —O(alkyl), —NH(alkyl), cycloalkyl, and heterocyclics are optionallysubstituted with one or more groups selected from OH, CN, halogen, oxo,CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl, wherein the phenyl isoptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h); and (2) thealkyl, phenyl, heteroaryls and aryl are optionally substituted with oneor more groups selected from OH, CN, halogen, CF₃, cyclopropyl,cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆alkyl), NR^(e)R^(f) and phenyl, wherein the phenyl is optionallysubstituted with one or more groups selected from OH, CN, halogen, CF₃,C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(e)R^(h).

In certain embodiments, R² is selected from C₁-C₆ alkyl, —O(C₁-C₆alkyl), —NH(C₁-C₆ alkyl), C₂-C₆ alkanoylalkyl, a saturated or partiallyunsaturated C₃-C₆ cycloalkyl, phenyl, a saturated or partiallyunsaturated 4 to 6 membered heterocyclic, a 5 or 6 membered heteroaryl,an 8 to 10 membered bicyclic aryl, an 8 to 10 membered bicyclicheterocyclic, and an 8 to 10 membered bicyclic heteroaryl, wherein: (1)the —O(alkyl), —NH(alkyl), cycloalkyl, and heterocyclics are optionallysubstituted with one or more groups selected from OH, CN, halogen, oxo,CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl; and (2) the alkyl,phenyl, heteroaryls and aryl are optionally substituted with one or moregroups selected from OH, CN, halogen, CF₃, cyclopropyl,cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆alkyl), NR^(e)R^(f), and phenyl.

In certain embodiments, R² is selected from C₁-C₆ alkyl, —O(C₁-C₆alkyl), —NH(C₁-C₆ alkyl), C₂-C₆ alkanoylalkyl, a saturated C₃-C₆cycloalkyl, phenyl, a saturated or partially unsaturated 4 to 6 memberedheterocyclic, a 5 or 6 membered heteroaryl, and an 8 to 10 memberedbicyclic heteroaryl, wherein: (1) the —O(alkyl), —NH(alkyl), cycloalkyl,and heterocyclics are optionally substituted with one or more groupsselected from OH, CN, halogen, oxo, CF₃, cyclopropyl, cyclopropylmethyl,—SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), and phenyl; and (2) the alkyl,phenyl, heteroaryls and aryl are optionally substituted with one or moregroups selected from OH, CN, halogen, CF₃, cyclopropyl,cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), and phenyl.

In the present invention, R² may be optionally substituted C₁-C₆ alkyl,—O(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), a saturated or partially unsaturatedC₃-C₆ cycloalkyl, phenyl, a saturated or partially unsaturated 4 to 6membered heterocyclic, a 5 or 6 membered heteroaryl, an 8 to 10 memberedbicyclic aryl, an 8 to 10 membered bicyclic heterocyclic, or an 8 to 10membered bicyclic heteroaryl. These optional substitutions include anoxo substituent. This oxo substituent may not be a substituent if R² isphenyl, aryl or heteroaryl. Thus, “oxo (except not on phenyl, aryl orheteroaryl)” means that the oxo substituent is not an optionalsubstituent for phenyl, aryl or heteroaryl.

In certain embodiments, R² is C₁-C₆ alkyl optionally substituted withone or more groups selected from OH, CN, halogen, oxo, CF₃, cyclopropyl,cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆alkyl), NR^(e)R^(f), and phenyl, wherein the phenyl is optionallysubstituted with one or more groups selected from OH, CN, halogen, CF₃,C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h). In certain embodiments,R² is C₁-C₆ alkyl optionally substituted with one or more groupsselected from OH, CN, halogen, oxo, CF₃, cyclopropyl, cyclopropylmethyl,—SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f),and phenyl. In certain embodiments, R² is C₁-C₆ alkyl optionallysubstituted with one or more groups selected from OH, CN, halogen, oxo,CF₃, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), andNR^(e)R^(f), and phenyl. In certain embodiments, R² is C₁-C₆ alkyloptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, cyclopropyl, —SO₂R^(i), —O(C₁-C₆ alkyl), and phenyl. Incertain embodiments, R² is C₁-C₆ alkyl optionally substituted with—O(C₁-C₆ alkyl), wherein the —O(C₁-C₆ alkyl) is methoxy (—OCH₃), ethoxy(—OCH₂CH₃), or isopropoxy (—OCH(CH₃)₂). In certain embodiments, R² isC₁-C₆ alkyl optionally substituted with cyclopropyl. In certainembodiments, R² is C₁-C₆ alkyl optionally substituted with —SO₂R^(i),wherein R^(i) is C₁-C₃ alkyl. In certain embodiments, R² is selectedfrom methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl(—CH₂CH(CH₃)₂), cyclopropylmethyl, —CH₂CF₃, —CH(CH₂CH₃)₂, —CH₂OH,—CH₂OCH₃, —CH₂OCH₂CH₃, —CH(CH₃)OCH₃, —CH₂CH₂OCH₃, —CH(CH₃)OH,—C(CH₃)₂OH, —CH₂CN, —CH₂CH₂F, —C(CH₃)₂F, —CH(CH₃)CH₂CH₃, —CH₂OCH(CH₃)₂,—CH(CH₃)OCH(CH₃)₂, —CH₂SO₂CH₃, —CH(CH₃)phenyl, and —CH₂(phenyl).

In certain embodiments, R² is C₁-C₆ alkyl optionally substituted withone or more groups selected from OH, CN, halogen, oxo, CF₃, C₁-C₆ alkyl,—O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), and NR^(e)R^(f) In certainembodiments, R² is C₁-C₆ alkyl optionally substituted with one or moregroups selected from oxo, CF₃, —O(C₁-C₆ alkyl), or C₃-C₆ cycloalkyl. Incertain embodiments, R² is C₁-C₆ alkyl optionally substituted with oxo.In certain embodiments, R² is C₁-C₆ alkyl optionally substituted with—O(C₁-C₆ alkyl), wherein the —O(C₁-C₆ alkyl) is methoxy (—OCH₃). Incertain embodiments, R² is C₁-C₆ alkyl optionally substituted with C₃-C₆cycloalkyl, wherein the C₃-C₆ cycloalkyl is cyclopropyl. In certainembodiments, R² is selected from isopropyl, tert-butyl, isobutyl(—CH₂CH(CH₃)₂), cyclopropylmethyl, —CH(CH₂CH₃)₂, —CH₂OCH₃, —CH(CH₃)OCH₃,—CH₂CH₂OCH₃, and —C(cyclopropyl)CF₃.

In certain embodiments, R² is C₁-C₆ alkyl. In certain embodiments, R² isselected from methyl, ethyl, propyl, isopropyl, tert-butyl, isobutyl,—CH(CH₂CH₃)₂ and —CH(CH₃)CH₂CH₃.

In certain embodiments, R² is C₁-C₆ alkyl. In certain embodiments, R² isselected from isopropyl, tert-butyl, isobutyl, and —CH(CH₂CH₃)₂.

In certain embodiments, R² is C₁-C₆ alkyl substituted with one or moregroups selected from OH, CN, halogen, oxo, CF₃, cyclopropyl,cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆alkyl), NR^(e)R^(f) and phenyl, wherein the phenyl is optionallysubstituted with one or more groups selected from OH, CN, halogen, CF₃,C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h). In certain embodiments,R² is C₁-C₆ alkyl substituted with one or more groups selected from OH,CN, halogen, oxo, CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl. Incertain embodiments, R² is C₁-C₆ alkyl substituted with one or moregroups selected from OH, CN, halogen, CF₃, cyclopropyl, —SO₂R^(i),—O(C₁-C₆ alkyl), and phenyl. In certain embodiments, R² is C₁-C₆ alkyloptionally substituted with —O(C₁-C₆ alkyl), wherein the —O(C₁-C₆ alkyl)is methoxy, ethoxy or isopropoxy. In certain embodiments, R² is C₁-C₆alkyl substituted with cyclopropyl. In certain embodiments, R² is C₁-C₆alkyl optionally substituted with —SO₂R^(i), wherein R¹ is C₁-C₃ alkyl.In certain embodiments, R² is C₁-C₆ alkyl optionally substituted withphenyl. In certain embodiments, R² is cyclopropylmethyl, —CH₂CF₃,—CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH(CH₃)OCH₃, —CH₂CH₂OCH₃, —CH(CH₃)OH,—C(CH₃)₂OH, —CH₂CN, —CH₂CH₂F, —C(CH₃)₂F, —CH(CH₃)CH₂CH₃, —CH₂OCH(CH₃)₂,—CH(CH₃)OCH(CH₃)₂, —CH₂SO₂CH₃, —CH(CH₃)phenyl, and —CH₂(phenyl).

In certain embodiments, R² is C₁-C₆ alkyl substituted with one or moregroups selected from OH, CN, halogen, oxo, CF₃, C₁-C₆ alkyl, —O(C₁-C₆alkyl), —S(C₁-C₆ alkyl), and NR^(e)R^(f). In certain embodiments, R² isC₁-C₆ alkyl substituted with one or more groups selected from oxo, CF₃,—O(C₁-C₆ alkyl), or C₃-C₆ cycloalkyl. In certain embodiments, R² isC₁-C₆ alkyl optionally substituted with oxo. In certain embodiments, R²is C₁-C₆ alkyl optionally substituted with —O(C₁-C₆ alkyl), wherein the—O(C₁-C₆ alkyl) is methoxy. In certain embodiments, R² is C₁-C₆ alkylsubstituted with C₃-C₆ cycloalkyl, wherein the C₃-C₆ cycloalkyl iscyclopropyl. In certain embodiments, R² is C₁-C₆ alkyl substituted withoxo and —O(C₁-C₆ alkyl). In certain embodiments, R² is C₁-C₆ alkylsubstituted with oxo and —O(C₁-C₆ alkyl), wherein the —O(C₁-C₆ alkyl) ismethoxy. In certain embodiments, R² is C₁-C₆ alkyl substituted with oxo,CF₃, and C₃-C₆ cycloalkyl. In certain embodiments, R² is C₁-C₆ alkylsubstituted with oxo, CF₃, and C₃-C₆ cycloalkyl, wherein the C₃-C₆cycloalkyl is cyclopropyl. In certain embodiments, R² iscyclopropylmethyl, —CH₂OCH₃, —CH(CH₃)OCH₃, —CH₂CH₂OCH₃, and—C(cyclopropyl)CF₃.

In certain embodiments, R² is —O(C₁-C₆ alkyl), wherein the alkyl isoptionally substituted with one or more groups selected from OH, CN,halogen, oxo, CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl,wherein the phenyl is optionally substituted with one or more groupsselected from OH, CN, halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), andNR^(g)R^(h). In certain embodiments, R² is —O(C₁-C₆ alkyl). In certainembodiments, R² is —OCH₂CH₃.

In certain embodiments, R² is —NH(C₁-C₆ alkyl), wherein the alkyl isoptionally substituted with one or more groups selected from OH, CN,halogen, oxo, CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl,wherein the phenyl is optionally substituted with one or more groupsselected from OH, CN, halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), andNR^(g)R^(h). In certain embodiments, R² is —NH(C₁-C₆ alkyl). In certainembodiments, R² is —NH(CH₂CH₃).

In certain embodiments, R² is a C₂-C₆ alkanoylalkyl optionallysubstituted with one or more groups selected from OH, CN, halogen, CF₃,cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl),—S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl, wherein the phenyl isoptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h). In certainembodiments, R² is a C₂-C₆ alkanoylalkyl optionally substituted with oneor more groups selected from OH, CN, halogen, CF₃, cyclopropyl,cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆alkyl), NR^(e)R^(f), and phenyl. In certain embodiments, R² is a C₂-C₆alkanoylalkyl.

In certain embodiments, R² is a saturated or partially unsaturated C₃-C₆cycloalkyl optionally substituted with one or more groups selected fromOH, CN, halogen, oxo, CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i),C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl,wherein the phenyl is optionally substituted with one or more groupsselected from OH, CN, halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), andNR^(g)R^(h). In certain embodiments, R² is a saturated or partiallyunsaturated C₃-C₆ cycloalkyl optionally substituted with one or moregroups selected from OH, CN, halogen, oxo, CF₃, cyclopropyl,cyclopropylmethyl, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl),NR^(e)R^(f), and phenyl. In certain embodiments, R² is a saturated orpartially unsaturated C₃-C₆ cycloalkyl optionally substituted with oneor more groups selected from halogen, CF₃, C₁-C₆ alkyl, —O(C₁-C₆ alkyl),and phenyl. In certain embodiments, R² is a saturated C₃-C₆ cycloalkyloptionally substituted with one or more groups selected from halogen,CF₃, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), and phenyl. In certain embodiments,R² is selected from cyclopropyl, cyclobutyl, cyclopentyl,1-(trifluoromethyl)cyclopropyl, 1-(methoxy)cyclopropyl,2,2-difluorocyclopropyl, 1-methylcyclopropyl, 2-phenylcyclopropyl, and2,2-dimethylcyclopropyl.

In certain embodiments, R² is a saturated or partially unsaturated C₃-C₆cycloalkyl optionally substituted with one or more groups selected fromOH, CN, halogen, oxo, CF₃, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆alkyl), and NR^(e)R^(f). In certain embodiments, R² is a saturated orpartially unsaturated C₃-C₆ cycloalkyl. In certain embodiments, R² is asaturated C₃-C₆ cycloalkyl. In certain embodiments, R² is selected fromcyclopropyl, cyclobutyl and cyclopentyl.

In certain embodiments, R² is phenyl optionally substituted with one ormore groups selected from OH, CN, halogen, CF₃, cyclopropyl,cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆alkyl), NR^(e)R^(f), and phenyl, wherein the phenyl is optionallysubstituted with one or more groups selected from OH, CN, halogen, CF₃,C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h). In certain embodiments,R² is phenyl optionally substituted with one or more groups selectedfrom OH, CN, halogen, CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i),C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl.In certain embodiments, R² is phenyl optionally substituted with one ormore groups selected from halogen, CF₃, C₁-C₆ alkyl or —O(C₁-C₆ alkyl).In certain embodiments, R² is phenyl substituted with halogen, whereinthe halogen is F or Cl. In certain embodiments, R² is phenyl substitutedwith —O(C₁-C₆ alkyl), wherein the —O(C₁-C₆ alkyl) is methoxy. In certainembodiments, R² is selected from phenyl, 3-methylphenyl, 4-fluorophenyl,3-methoxyphenyl, 3-fluorophenyl, 3-chloro-4-fluorophenyl,3-fluoro-4-methoxyphenyl, 3-trifluoromethylphenyl, and2-fluoro-5-methylphenyl.

In certain embodiments, R² is phenyl optionally substituted with one ormore groups selected from OH, CN, halogen, CF₃, C₁-C₆ alkyl, —O(C₁-C₆alkyl), —S(C₁-C₆ alkyl), and NR^(e)R^(f). In certain embodiments, R² isphenyl optionally substituted with one or more groups selected fromhalogen, CF₃, C₁-C₆ alkyl or —O(C₁-C₆ alkyl). In certain embodiments, R²is phenyl substituted with halogen, wherein the halogen is F or Cl. Incertain embodiments, R² is phenyl substituted with CF₃. In certainembodiments, R² is phenyl substituted with C₁-C₆ alkyl, wherein theC₁-C₆ alkyl is methyl. In certain embodiments, R² is phenyl substitutedwith —O(C₁-C₆ alkyl), wherein the —O(C₁-C₆ alkyl) is methoxy. In certainembodiments, R² is selected from phenyl, 3-methylphenyl, 4-fluorophenyl,3-methoxyphenyl, 3-fluorophenyl, 3-chloro-4-fluorophenyl,3-fluoro-4-methoxyphenyl, 3-trifluoromethylphenyl, and2-fluoro-5-methylphenyl.

In certain embodiments, R² is phenyl optionally substituted with twogroups selected from halogen, C₁-C₆ alkyl or —O(C₁-C₆ alkyl). In certainembodiments, R² is phenyl substituted with halogen, wherein the halogenis F or Cl. In certain embodiments, R² is phenyl substituted with C₁-C₆alkyl, wherein the C₁-C₆ alkyl is methyl. In certain embodiments, R² isphenyl substituted with —O(C₁-C₆ alkyl), wherein the —O(C₁-C₆ alkyl) ismethoxy. In certain embodiments, R² is selected from3-chloro-4-fluorophenyl, 3-fluoro-4-methoxyphenyl, and2-fluoro-5-methylphenyl.

In certain embodiments, R² is a saturated or partially unsaturated 4 to6 membered heterocyclic optionally substituted with one or more groupsselected from OH, CN, halogen, oxo, CF₃, cyclopropyl, cyclopropylmethyl,—SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f),and phenyl, wherein the phenyl is optionally substituted with one ormore groups selected from OH, CN, halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃alkyl), and NR^(g)R^(h). In certain embodiments, R² is a saturated orpartially unsaturated 4 to 6 membered heterocyclic optionallysubstituted with one or more groups selected from OH, CN, halogen, oxo,CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl. In certainembodiments, R² is a saturated or partially unsaturated 4 to 6 memberedheterocyclic optionally substituted with one or more groups selectedfrom OH, oxo, cyclopropylmethyl, and C₁-C₆ alkyl. In certainembodiments, R² is a saturated 4 to 6 membered heterocyclic containingone or two heteroatoms selected from nitrogen and oxygen, wherein theheterocyclic is optionally substituted with oxo. In certain embodiments,R² is a saturated 4 to 6 membered heterocyclic optionally substitutedwith oxo, wherein the heterocyclic is selected from oxetanyl,tetrahydrofuranyl, morpholinyl and pyrrolidinyl. In certain embodiments,R² is a partially unsaturated 4 to 6 membered heterocyclic optionallysubstituted with oxo or C₁-C₆ alkyl. In certain embodiments, R² is apartially unsaturated 4 to 6 membered heterocyclic containing one or twonitrogen heteroatoms, wherein the heterocyclic is optionally substitutedwith oxo or C₁-C₆ alkyl. In certain embodiments, R² is a partiallyunsaturated 6 membered heterocyclic optionally substituted with halogen,oxo or C₁-C₆ alkyl, wherein the heterocyclic is selected from1,2-dihydropyridine and 1,6-dihydropyridazine. In certain embodiments,R² is 1,2-dihydropyridine or 1,6-dihydropyridazine optionallysubstituted with halogen, oxo, or C₁-C₃ alkyl. In certain embodiments,R² is selected from 3-methyloxetan-3-yl, azetidin-1-yl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl,1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl,1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridazin-3-yl, morpholin-2-yl,pyrrolidin-1-yl and 5-oxopyrrolidin-2-yl.

In certain embodiments, R² is a saturated or partially unsaturated 5 or6 membered heterocyclic optionally substituted with one or more groupsselected from OH, CN, halogen, oxo, CF₃, C₁-C₆ alkyl, —O(C₁-C₆ alkyl),—S(C₁-C₆ alkyl), and NR^(e)R^(f). In certain embodiments, R² is asaturated or partially unsaturated 5 or 6 membered heterocyclicoptionally substituted with oxo or C₁-C₆ alkyl. In certain embodiments,R² is a saturated 5 or 6 membered heterocyclic. In certain embodiments,R² is a saturated 5 or 6 membered heterocyclic containing one or twoheteroatoms selected from nitrogen and oxygen. In certain embodiments,R² is a saturated 5 or 6 membered heterocyclic, wherein the heterocyclicis selected from tetrahydrofuranyl and morpholinyl. In certainembodiments, R² is a saturated 5 membered heterocyclic containing anoxygen heteroatom. In certain embodiments, R² is a saturated 5 memberedheterocyclic, wherein the heterocyclic is tetrahydrofuran. In certainembodiments, R² is a saturated 6 membered heterocyclic containing one ortwo heteroatoms selected from oxygen and nitrogen. In certainembodiments, R² is a saturated 6 membered heterocyclic, wherein theheterocyclic is morpholinyl. In certain embodiments, R² is a partiallyunsaturated 5 or 6 membered heterocyclic optionally substituted with oxoor C₁-C₆ alkyl. In certain embodiments, R² is a partially unsaturated 5or 6 membered heterocyclic containing one or two nitrogen heteroatoms,wherein the heterocyclic is optionally substituted with oxo or C₁-C₆alkyl. In certain embodiments, R² is a partially unsaturated 6 memberedheterocyclic containing one or two nitrogen heteroatoms, wherein theheterocyclic is optionally substituted with oxo or C₁-C₆ alkyl. Incertain embodiments, R² is a partially unsaturated 6 memberedheterocyclic optionally substituted with halogen, oxo or C₁-C₆ alkyl,wherein the heterocyclic is selected from 1,2-dihydropyridine and1,-6-dihydropyridazine. In certain embodiments, R² is a partiallyunsaturated 6 membered heterocyclic optionally substituted with oxo andC₁-C₆ alkyl, wherein the heterocyclic is selected from1,2-dihydropyridine and 1,6-dihydropyridazine. In certain embodiments,R² is 1,2-dihydropyridine or 1,6-dihydropyridazine optionallysubstituted with halogen, oxo, or C₁-C₃ alkyl. In certain embodiments,R² is 1,2-dihydropyridine or 1,6-dihydropyridazine substituted with oxoand C₁-C₃ alkyl. In certain embodiments, R² is selected fromtetrahydrofuran-2-yl, tetrahydrofuran-3-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl and morpholin-2-yl.

In certain embodiments, R² is a saturated 5 or 6 membered heterocyclicoptionally substituted with one or more groups selected from OH, CN,halogen, oxo, CF₃, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), andNR^(e)R^(f). In certain embodiments, R² is a saturated 5 or 6 memberedheterocyclic optionally substituted with oxo or C₁-C₆ alkyl. In certainembodiments, R² is a saturated 5 or 6 membered heterocyclic. In certainembodiments, R² is a saturated 5 or 6 membered heterocyclic containingone or two heteroatoms selected from nitrogen and oxygen. In certainembodiments, R² is a saturated 5 membered heterocyclic. In certainembodiments, R² is a saturated 5 membered heterocyclic containing anoxygen heteroatom. In certain embodiments, R² is a saturated 5 memberedheterocyclic, wherein the heterocyclic is tetrahydrofuran. In certainembodiments, R² is a saturated 6 membered heterocyclic. In certainembodiments, R² is a saturated 6 membered heterocyclic containing one ortwo heteroatoms selected from nitrogen and oxygen. In certainembodiments, R² is a saturated 6 membered heterocyclic containing twoheteroatoms selected from nitrogen and oxygen. In certain embodiments,R² is a saturated 6 membered heterocyclic, wherein the heterocyclic ismorpholinyl. In certain embodiments, R² is tetrahydrofuran-2-yl,tetrahydrofuran-3-yl or morpholin-2-yl.

In certain embodiments, R² is a partially unsaturated 5 or 6 memberedheterocyclic optionally substituted with one or more groups selectedfrom OH, CN, halogen, oxo, CF₃, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆alkyl), and NR^(e)R^(f). In certain embodiments, R² is a partiallyunsaturated 5 or 6 membered heterocyclic optionally substituted with oxoor C₁-C₆ alkyl. In certain embodiments, R² is a partially unsaturated 5or 6 membered heterocyclic containing one or two nitrogen heteroatoms,wherein the heterocyclic is optionally substituted with oxo or C₁-C₆alkyl. In certain embodiments, R² is a partially unsaturated 6 memberedheterocyclic containing one or two nitrogen heteroatoms, wherein theheterocyclic is optionally substituted with oxo or C₁-C₆ alkyl. Incertain embodiments, R² is a partially unsaturated 6 memberedheterocyclic optionally substituted with oxo or C₁-C₆ alkyl, wherein theheterocyclic is selected from 1,2-dihydropyridine and1,-6-dihydropyridazine. In certain embodiments, R² is1,2-dihydropyridine or 1,6-dihydropyridazine optionally substituted withhalogen, oxo, or C₁-C₃ alkyl. In certain embodiments, R² is1,2-dihydropyridine or 1,6-dihydropyridazine substituted with oxo andC₁-C₃ alkyl. In certain embodiments, R² is selected from1-methyl-6-oxo-1,6-dihydropyridin-3-yl and1-methyl-6-oxo-1,6-dihydropyridazin-3-yl.

In certain embodiments, R² is a 5 or 6 membered heteroaryl optionallysubstituted with one or more groups selected from OH, CN, halogen, CF₃,cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl),—S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl, wherein the phenyl isoptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h). In certainembodiments, R² is a 5 or 6 membered heteroaryl optionally substitutedwith one or more groups selected from OH, CN, halogen, CF₃, cyclopropyl,cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆alkyl), NR^(e)R^(f), and phenyl. In certain embodiments, R² is a 5 or 6membered heteroaryl optionally substituted with halogen, CF₃, C₁-C₆alkyl or —O(C₁-C₆ alkyl). In certain embodiments, R² is a 5 or 6membered heteroaryl optionally substituted with halogen, CF₃, C₁-C₆alkyl or —O(C₁-C₆ alkyl), wherein the heteroaryl contains 1 or 2heteroatoms selected from nitrogen, oxygen and sulfur. In certainembodiments, R² is a 5 or 6 membered heteroaryl optionally substitutedwith halogen, CF₃, C₁-C₆ alkyl or —O(C₁-C₆ alkyl), wherein theheteroaryl is selected from pyrazole, oxazole, isoxazole, thiazole,pyridine, pyrimidine and pyrazine. In certain embodiments, R² is a 5 or6 membered heteroaryl optionally substituted with halogen, wherein thehalogen is Cl or F. In certain embodiments, R² is a 5 or 6 memberedheteroaryl optionally substituted with C₁-C₆ alkyl, wherein the C₁-C₆alkyl is methyl or ethyl. In certain embodiments, R² is a 5 or 6membered heteroaryl optionally substituted with —O(C₁-C₆ alkyl), whereinthe C₁-C₆ alkyl is methoxy. In certain embodiments, R² is selected frompyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl,2-methyloxazol-4-yl, 5-methylisoxazol-3-yl, 2-methylthiazol-4-yl,pyridin-2-yl, pyridin-3-yl, 6-methoxy-pyridin-2-yl,3-methylpyridin-2-yl, 5-chloro-pyridin-2-yl,5-trifluoromethylpyridin-2-yl, 2-methylpyridin-3-yl,5-methylpyridin-3-yl, 5-chloropyridin-3-yl, 6-methylpyridin-3-yl,pyrimidin-2-yl, 5-ethylpyrimidin-2-yl, pyrazin-2-yl, and5-methylpyrazin-2-yl.

In certain embodiments, R² is a 5 or 6 membered heteroaryl optionallysubstituted with one or more groups selected from OH, CN, halogen, CF₃,C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), and NR^(e)R^(f). Incertain embodiments, R² is a 5 or 6 membered heteroaryl optionallysubstituted with halogen, C₁-C₆ alkyl or —O(C₁-C₆ alkyl). In certainembodiments, R² is a 5 or 6 membered heteroaryl optionally substitutedwith halogen, C₁-C₆ alkyl or —O(C₁-C₆ alkyl), wherein the heteroarylcontains 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur.In certain embodiments, R² is a 5 or 6 membered heteroaryl optionallysubstituted with halogen, C₁-C₆ alkyl or —O(C₁-C₆ alkyl), wherein theheteroaryl is selected from pyrazole, oxazole, isoxazole, thiazole,pyridine, pyrimidine and pyrazine. In certain embodiments, R² is a 5 or6 membered heteroaryl optionally substituted with halogen, wherein thehalogen is Cl or F. In certain embodiments, R² is a 5 or 6 memberedheteroaryl optionally substituted with halogen, wherein the halogen isCl. In certain embodiments. R² is a 5 or 6 membered heteroaryloptionally substituted with C₁-C₆ alkyl, wherein the C₁-C₆ alkyl ismethyl. In certain embodiments, R² is a 5 or 6 membered heteroaryloptionally substituted with —O(C₁-C₆ alkyl), wherein the C₁-C₆ alkyl ismethoxy. In certain embodiments, R² is selected from pyrazol-4-yl,1-methyl-1H-pyrazol-3-yl, 2-methyloxazol-4-yl, 5-methylisoxazol-3-yl,2-methylthiazol-4-yl, pyridin-2-yl, pyridin-3-yl,6-methoxy-pyridin-2-yl, 3-methylpyridin-2-yl, 5-chloro-pyridin-2-yl,5-methylpyridin-2-yl, 2-methylpyridin-3-yl, 5-methylpyridin-3-yl,5-chloropyridin-3-yl, 6-methylpyridin-3-yl, pyrimidin-2-yl,pyrazin-2-yl, and 5-methylpyrazin-2-yl.

In certain embodiments, R² is an 8 to 10 membered bicyclic heteroaryloptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl,—O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl, wherein thephenyl is optionally substituted with one or more groups selected fromOH, CN, halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h). Incertain embodiments, R² is an 8 to 10 membered bicyclic heteroaryloptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl,—O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl. In certainembodiments, R² is an 8 to 10 membered bicyclic heteroaryl. In certainembodiments, R² is an 8 to 10 membered bicyclic heteroaryl containingone or two nitrogen heteroatoms. In certain embodiments, R² is an 8 to10 membered bicyclic heteroaryl, wherein the heteroaryl is quinoxaline.In certain embodiments, R² is quinoxalin-2-yl.

In certain embodiments, R² is an 8 to 10 membered bicyclic heteroaryloptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), andNR^(e)R^(f). In certain embodiments, R² is an 8 to 10 membered bicyclicheteroaryl. In certain embodiments, R² is an 8 to 10 membered bicyclicheteroaryl containing two nitrogen heteroatoms. In certain embodiments,R² is an 8 to 10 membered bicyclic heteroaryl, wherein the heteroaryl isquinoxaline. In certain embodiments, R² is quinoxalin-2-yl.

In certain embodiments, R³ and R⁴ are independently selected fromhydrogen or C₁-C₄ alkyl optionally substituted with OH, F, —O(C₁-C₃alkyl) or C₃-C₆ cycloalkyl.

In certain embodiments, R³ and R⁴ are independently selected fromhydrogen, methyl, ethyl, isopropyl, isobutyl, CH₂CH₂OH, CH₂CH₂OCH₃,CH₂CH₂F and cyclopropylmethyl.

In certain embodiments, R³ is selected from hydrogen, methyl, ethyl,isopropyl, isobutyl, CH₂CH₂OH, CH₂CH₂OCH₃, CH₂CH₂F andcyclopropylmethyl, and R⁴ is selected from hydrogen and methyl.

In certain embodiments, R³ is selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F, —O(C₁-C₃ alkyl) or C₃-C₆ cycloalkyl.In certain embodiments, R³ is selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F, —O(C₁-C₃ alkyl) or C₃-C₆ cycloalkyl,wherein the cycloalkyl is cyclopropyl. In certain embodiments, R³ isselected from hydrogen, methyl, ethyl, isopropyl, isobutyl, CH₂CH₂OH,CH₂CH₂OCH₃, CH₂CH₂F and cyclopropylmethyl.

In certain embodiments, R³ is selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F or C₃-C₆ cycloalkyl. In certainembodiments, R³ is selected from hydrogen, methyl, isopropyl, isobutyl,CH₂CH₂OH and cyclopropylmethyl.

In certain embodiments, R³ is selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH or C₃-C₆ cycloalkyl. In certainembodiments, R³ is selected from hydrogen or C₁-C₄ alkyl optionallysubstituted with OH or C₃-C₆ cycloalkyl, wherein the cycloalkyl iscyclopropyl. In certain embodiments, R³ is selected from hydrogen,methyl, isopropyl, isobutyl, CH₂CH₂OH and cyclopropylmethyl(—CH₂-cyclopropyl).

In certain embodiments, R⁴ is selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F or C₃-C₆ cycloalkyl. In certainembodiments, R⁴ is selected from hydrogen and methyl.

In certain embodiments, R⁴ is selected from hydrogen and C₁-C₄ alkyloptionally substituted with OH or C₃-C₆ cycloalkyl. In certainembodiments, R⁴ is selected from hydrogen and C₁-C₄ alkyl. In certainembodiments, R⁴ is selected from hydrogen and methyl.

In certain embodiments, R³ and R⁴ together with the atoms to which theyare attached form a 5 or 6 membered ring, as shown in the structure:

wherein the wavy line represents where the nitrogen attaches to A and wis 1 or 2. As R³ and R⁴ are both attached to a nitrogen, this 5 or 6membered ring is a heterocyclic ring.

In certain embodiments, A is selected from a direct bond or CR^(a)R^(b).In certain embodiments, R^(a) is hydrogen. In certain embodiments, R^(b)is hydrogen or absent.

In certain embodiments, A is a direct bond, as shown in Formula IIIa:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(6a), R⁷ and p are as defined herein.

In certain embodiments, A is a direct bond and p is 1, as shown inFormula IIIb:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(6a) and R⁷ are as defined herein.

In certain embodiments, A is a direct bond and p is 2, as shown inFormula IIIc:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(6a) and R⁷ are as defined herein.

In certain embodiments, A is CR^(a)R^(b), as shown in Formula IVa:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(6a), R⁷, R^(a), R^(b) and p are asdefined herein.

In certain embodiments, A is CR^(a)R^(b) and p is 1, as shown in FormulaIVb:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R^(6a), R⁷, R^(a) and R^(b) are asdefined herein.

In certain embodiments, R⁴ and R^(b) are absent and R³ and R^(a)together with the atoms to which they are attached form an aromatic 5 or6 membered ring. As R³ is attached to a nitrogen atom, this aromatic 5or 6 membered ring is heteroaryl. In certain embodiments, R⁴ and R^(b)are absent and R³ and R^(a) together with the atoms to which they areattached form an aromatic 5 or 6 membered ring, wherein the aromaticring is heteroaryl and contains 1 nitrogen. In certain embodiments, R⁴and R^(b) are absent and R³ and R^(a) together with the atoms to whichthey are attached form an aromatic 5 or 6 membered ring, wherein thearomatic ring is selected from pyrrolyl and pyridinyl. In certainembodiments, R⁴ and R^(b) are absent and R³ and R^(a) together with theatoms to which they are attached form an aromatic 6 membered ring,wherein the aromatic 6 membered ring is pyridinyl. In certainembodiments, R⁴ and R^(b) are absent and R³ and R^(a) together with theatoms to which they are attached form a pyridinyl ring. In certainembodiments, R⁴ and R^(b) are absent and R³ and R^(a) together formpyridin-2-yl.

In certain embodiments, R⁵ is selected from hydrogen and CH₃. In certainembodiments, R⁵ is hydrogen. In certain embodiments, R⁵ is CH₃.

In certain embodiments, A is CR^(a)R^(b), R^(a) and R^(b) are hydrogen,and R³ and R⁵ together with the atoms to which they are attached form a5 or 6 membered ring, as shown in Formula Va:

wherein R¹, R², R⁴, R⁶, R^(6a), R⁷ and p are as defined herein, and q is1 or 2. As R³ is attached to a nitrogen atom, this 5 or 6 membered ringis heterocyclic. As R³ and R⁵ form a ring at a single atom of anotherring, the compounds of Formula I and Va contain a spirocyclic ring.

In certain embodiments of Formula Va, p is 1.

In certain embodiments of Formula Va, q is 1.

In certain embodiments of Formula Va, R⁴, R⁶, R^(6a) and R⁷ arehydrogen.

In certain embodiments, A is CR^(a)R^(b), R^(a) and R^(b) are hydrogen,and R³ and R⁵ together with the atoms to which they are attached form a5 membered ring, as shown in Formula Vb:

wherein R¹, R², R⁴, R⁶, R^(6a), R⁷ and p are as defined herein.

In certain embodiments of Formula Vb, p is 1.

In certain embodiments of Formula Vb, R⁴, R⁶, R^(6a) and R⁷ arehydrogen.

In certain embodiments, R⁶ is selected from hydrogen, F, OH, —OCH₃,C₁-C₃ alkyl and cyclopropyl.

In certain embodiments, R⁶ is selected from hydrogen, F, OH, —OCH₃ andC₁-C₃ alkyl. In certain embodiments, R⁶ is hydrogen.

In certain embodiments, R⁶ is selected from hydrogen, F, —OCH₃, methyland cyclopropyl.

In certain embodiments, R⁶ is hydrogen.

In certain embodiments, R⁶ is halogen. In certain embodiments, R⁶ is F.

In certain embodiments, R⁶ is —OCH₃.

In certain embodiments, R⁶ is C₁-C₃ alkyl. In certain embodiments, R⁶ ismethyl.

In certain embodiments, R⁶ is cyclopropyl.

In certain embodiments, A is a direct bond, R^(6a) is hydrogen and R³and R⁶ together with the atoms to which they are attached form a 5 or 6membered ring, as shown in Formula VIa:

wherein R¹, R², R⁴, R⁵, R⁷ and p are as defined herein, and s is 1 or 2.As R³ is attached to a nitrogen atom, this 5 or 6 membered ring isheterocyclic. As R³ and R⁶ form a ring at two mutually bonded atoms ofanother ring, the compounds of Formula I and VIa contain a bicyclicring.

In certain embodiments of Formula VIa, p is 1 or 2.

In certain embodiments of Formula VIa, p is 1.

In certain embodiments of Formula VIa, p is 2.

In certain embodiments of Formula VIa, s is 1.

In certain embodiments of Formula VIa, R⁴, R⁵ and R⁷ are hydrogen.

In certain embodiments, A is a direct bond, R^(6a) is hydrogen and R³and R⁶ together with the atoms to which they are attached form a 5membered ring, as shown in Formula VIb:

wherein R¹, R², R⁴, R⁵, R⁷ and p are as defined herein.

In certain embodiments of Formula VIb, p is 1 or 2.

In certain embodiments of Formula VIb, p is 1.

In certain embodiments of Formula VIb, p is 2.

In certain embodiments of Formula VIb, R⁴, R⁵ and R⁷ are hydrogen.

In certain embodiments, R^(6a) is selected from hydrogen, F, OH and CH₃.In certain embodiments, R^(6a) is hydrogen.

In certain embodiments, R^(6a) is hydrogen.

In certain embodiments, R⁷ is hydrogen.

In certain embodiments, A is CR^(a)R^(b) and R³ and R⁷ together with theatoms to which they are attached form a 5 or 6 membered ring, as shownin Formula VIIa:

wherein R¹, R², R⁴, R⁵, R⁶, R^(6a), R^(a), R^(b) and p are as definedherein, and t is 1 or 2. As R³ is attached to a nitrogen atom, this 5 or6 membered ring is heterocyclic. As R³ and R⁷ form a ring at twomutually bonded atoms of another ring, the compounds of Formula I andVIIa contain a bicyclic ring.

In certain embodiments of Formula VIIa, p is 1.

In certain embodiments of Formula VIIa, t is 1.

In certain embodiments of Formula VIIa, R⁴, R⁵, R⁶, R^(6a), R^(a) andR^(b) are hydrogen.

In certain embodiments, A is CR^(a)R^(b) and R³ and R⁷ together with theatoms to which they are attached form a 5 membered ring, as shown inFormula VIIb:

wherein R¹, R², R⁴, R⁵, R⁶, R^(6a), R^(a), R^(b) and p are as definedherein.

In certain embodiments of Formula VIIb, p is 1.

In certain embodiments of Formula VIIb, R⁴, R⁵, R⁶, R^(6a), R^(a) andR^(b) are hydrogen.

In certain embodiments, R^(c) and R^(d) are independently selected fromhydrogen and C₁-C₃ alkyl.

In certain embodiments, R^(c) and R^(d) together with the atom to whichthey are attached from a 5 or 6 membered ring. As R^(c) and R^(d) areattached to a nitrogen atom, this 5 or 6 membered ring is heterocyclic.

In certain embodiments, R^(e) and R^(f) are independently selected fromhydrogen and C₁-C₃ alkyl.

In certain embodiments, R^(g) and R^(h) are independently selected fromhydrogen and C₁-C₃ alkyl.

In certain embodiments, R^(i) is C₁-C₃ alkyl. In certain embodiments,R^(i) is methyl.

Another embodiment of the present invention provides compounds ofFormula IXa:

and stereoisomers, tautomers and pharmaceutically acceptable saltsthereof, wherein:

R¹ is selected from Br, Cl, F, CF₃, ethyl, isopropyl, —OCH₂CH₃, —SCH₃,—SCH₂CH₃, —SCH(CH₃)₂, cyclopropyl, phenyl and 6-methylpyridin-3-yl;

R² is selected from ethyl, propyl, isopropyl, isobutyl,cyclopropylmethyl, —CH₂OH, —CH₂OCH₃, —CH(CH₃)OCH₃, —CH₂CH₂OCH₃,—C(CH₃)₂OH, —C(cyclopropyl)OCH₃, —C(CH₃)₂F, —CH₂OCH(CH₃)₂, cyclopropyl,cyclobutyl, cyclopentyl, tetrahydrofuran-3-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl,1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl,1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridazin-3-yl, morpholin-2-yl,pyrimidin-2-yl and 5-ethylpyrimidin-2-yl; and

B is selected from the structures:

wherein the wavy line represents the point of attachment of B to thepyrrolopyridine of Formula IXa.

In certain embodiments of Formula IXa, R¹ is selected from Br, Cl, F,ethyl, isopropyl and —SCH₃.

Another embodiment of the present invention provides compounds ofFormula IXb:

and stereoisomers, tautomers and pharmaceutically acceptable saltsthereof, wherein:

R¹ is selected from Br, Cl, F, CF₃, ethyl, isopropyl, —OCH₂CH₃, —SCH₃,—SCH₂CH₃, —SCH(CH₃)₂, cyclopropyl, phenyl and 6-methylpyridin-3-yl;

R² is selected from ethyl, propyl, isopropyl, isobutyl,cyclopropylmethyl, —CH₂OH, —CH(CH₃)OCH₃, —CH₂CH₂OCH₃, —C(CH₃)₂OH,—C(cyclopropyl)OCH₃, —C(CH₃)₂F, —CH₂OCH(CH₃)₂, cyclopropyl, cyclobutyl,cyclopentyl, tetrahydrofuran-3-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl,1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl and1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridazin-3-yl; and

B is selected from the structures:

wherein the wavy line represents the point of attachment of B to thepyrrolopyridine of Formula IXb.

In certain embodiments of Formula IXb, R¹ is selected from Br, Cl, F,ethyl, isopropyl and —SCH₃.

Another embodiment of the present invention provides compounds ofFormula IXc:

and stereoisomers, tautomers and pharmaceutically acceptable saltsthereof, wherein:

R¹ is selected from Br, Cl, F, CF₃, ethyl, isopropyl, —OCH₂CH₃, —SCH₃,—SCH₂CH₃, —SCH(CH₃)₂, cyclopropyl, phenyl and 6-methylpyridin-3-yl;

R² is selected from ethyl, propyl, isopropyl, isobutyl,cyclopropylmethyl, —CH₂OH, —CH(CH₃)OCH₃, —C(CH₃)₂OH,—C(cyclopropyl)OCH₃, —C(CH₃)₂F, cyclopropyl, cyclobutyl, cyclopentyl,tetrahydrofuran-3-yl, 1-methyl-6-oxo-1,6-dihydropyridazin-3-yl; and B isselected from the structures:

wherein the wavy line represents the point of attachment of B to thepyrrolopyridine of Formula IXc.

In certain embodiments of Formula IXc, R¹ is selected from Br, Cl, F,ethyl, isopropyl and —SCH₃.

Another embodiment of the present invention provides compounds ofFormula IXd:

and stereoisomers, tautomers and pharmaceutically acceptable saltsthereof, wherein:

R¹ is selected from Br, Cl, F, CF₃, ethyl, isopropyl, —OCH₂CH₃, —SCH₃,—SCH₂CH₃, —SCH(CH₃)₂, cyclopropyl, phenyl and 6-methylpyridin-3-yl;

R² is selected from ethyl, isopropyl, and cyclopropyl; and

B is selected from the structures:

wherein the wavy line represents the point of attachment of B to thepyrrolopyridine of Formula IXd.

In certain embodiments of Formula IXd, R¹ is selected from Br, Cl, F,ethyl, isopropyl and —SCH₃.

Another embodiment of the present invention provides compounds ofFormula X:

and stereoisomers, tautomers and pharmaceutically acceptable saltsthereof, wherein:

A is selected from a direct bond or CR^(a)R^(b);

R²¹ is selected from halogen, C₃-C₆ cycloalkyl and C₁-C₆ alkyl, whereinthe alkyl is optionally substituted with one or more halogen groups;

R²² is selected from C₁-C₆ alkyl, saturated C₃-C₆ cycloalkyl, phenyl,saturated or partially unsaturated 5 or 6 membered heterocyclic, a 5 or6 membered heteroaryl, and an 8 to 10 membered bicyclic heteroaryl,wherein the alkyl, cycloalkyl, phenyl, heterocyclic and heteroaryl areoptionally substituted with halogen, oxo (except not on phenyl orheteroaryl), CF₃, C₁-C₆ alkyl, —O(C₁-C₆ alkyl) or C₃-C₆ cycloalkyl;

R²³ is selected from hydrogen or C₁-C₄ alkyl optionally substituted withOH or C₃-C₆ cycloalkyl;

R²⁴ is selected from hydrogen and C₁-C₄ alkyl;

R²⁵ is selected from hydrogen and CH₃, or

A is CR^(a)R^(b), R^(a) and R^(b) are hydrogen, and R²³ and R²⁵ togetherwith the atoms to which they are attached form a 5 or 6 membered ring;

R²⁶ is selected from hydrogen, or

A is a direct bond and R²³ and R²⁶ together with the atoms to which theyare attached form a 5 or 6 membered ring;

R²⁷ is selected from hydrogen, or

A is CR^(a)R^(b) and R²³ and R²⁷ together with the atoms to which theyare attached form a 5 or 6 membered ring;

R^(a) and R^(b) are hydrogen, or

R²⁴ and R^(b) are absent and R²³ and R^(a) together with the atoms towhich they are attached form an aromatic 5 or 6 membered ring; and

p is 0, 1, 2 or 3.

It will be appreciated that certain compounds of the invention maycontain asymmetric or chiral centers, and therefore exist in differentstereoisomeric forms. It is intended that all stereoisomeric forms ofthe compounds of the invention, including but not limited to,diastereomers, enantiomers and atropisomers, as well as mixtures thereofsuch as racemic mixtures, form part of the present invention.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

It will also be appreciated that certain compounds of Formula I may beused as intermediates for further compounds of Formula I.

It will be further appreciated that the compounds of the presentinvention may exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike, and it is intended that the invention embrace both solvated andunsolvated forms.

Synthesis of Compounds

Compounds of the present invention may be synthesized by syntheticroutes that include processes analogous to those well-known in thechemical arts, particularly in light of the description containedherein. The starting materials are generally available from commercialsources such as Sigma-Aldrich (St. Louis, Mo.), Alfa Aesar (Ward Hill,Mass.), or TCI (Portland, Oreg.), or are readily prepared using methodswell known to those skilled in the art (e.g., prepared by methodsgenerally described in Louis F. Fieser and Mary Fieser, Reagents forOrganic Synthesis. v. 1-23, New York: Wiley 1967-2006 ed. (alsoavailable via the Wiley InterScience® website), or Beilsteins Handbuchder organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, includingsupplements (also available via the Beilstein online database)).

For illustrative purposes, Schemes 1-5 show a general method forpreparing the compounds of the present invention as well as keyintermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used to synthesizethe inventive compounds. Although specific starting materials andreagents are depicted in the Schemes and discussed below, other startingmaterials and reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Scheme 1 shows a general scheme for the synthesis of compound 6, whereinR^(1a) is halogen or CF₃. Compound 3, wherein PG is a protecting group,such as Boc, CBz, benzyl, phenylsulfonamide or silyl, and X¹ is Cl, maybe prepared as described in L'Heureux, Alexandre, et al., “Synthesis offunctionalized 7-azaindoles via directed ortho-metalations.” TetrahedronLett. 45 (2004): 2317-2319, and Thibault, Carl, et al., “Concise andefficient synthesis of 4-fluoro-1H-pyrrolo[2,3-b]pyridine.” OrganicLett. 5 (2003): 5023-5025. Compound 3 may be functionalized to installR^(1a) via lithiation under standard conditions (e.g., s-BuLi in anappropriate solvent such as tetrahydrofuran (“THF”)) and trapping with asuitable electrophile (CBr₄, I₂, perbromomethane,N-fluoro-N(phenylsulfonyl)benzenesulfonamide, etc.) to give compound 4,wherein R^(1a) is halogen. Compound 4 may optionally be furtherfunctionalized via copper-mediated coupling to provide compound 5. Theprotecting group may be removed under standard conditions (for example,tetra-N-butylammonium fluoride (“TBAF”) to remove a silyl group) toprovide compound 6.

In Scheme 1, R^(1a) may also be OH, and R^(1b) may also be —O(C₁-C₆alkyl), wherein the alkyl may be optionally substituted with one or moregroups selected from halogen, CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) andNR^(c)R^(d). Compound 3 may be functionalized to install R^(1a) vialithiation under standard conditions and trapping with(1S)-(+)-(10-camphorsulfonyl)oxaziridine gives compound 4, whereinR^(1a) is OH. Compound 4 may optionally be alkylated to provide compound5, wherein R^(1b) is —O(C₁-C₆ alkyl), wherein the alkyl may beoptionally substituted with one or more groups selected from halogen,CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d).

Scheme 2 shows a general scheme for the synthesis of compound 9, whereinR^(1b) and R² are as defined herein. Nitration of compound 6 can becarried out to give compound 7, which can then be reduced to the amine8. Coupling of amine 8 with an appropriate acid in the presence of acoupling reagent (such as2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(“HBTU”), bis(2-oxooxazolidin-3-yl)phosphinic chloride (“BOP-Cl”)) or anacid chloride in the presence of a base (such as pyridine,triethylamine, N,N-diisopropylethylamine (“Hunig's base” or “DIEA”))gives compound 9.

Scheme 3 shows a general scheme for the synthesis of compounds 10 and 11(both are subsets of Formula I), wherein R^(1b), R², R³, R⁶, R^(6a), R⁷,A and p are as defined herein and R^(4a) is C₁-C₄ alkyl. Compound 9 canbe converted to compound 10 by reaction with an appropriatelysubstituted amine, wherein PG is a protecting group, such as Boc, CBz,benzyl, or R⁴ as defined herein (when PG is R⁴ deprotection is notneeded), under standard S_(N)Ar reaction conditions. Deprotection ofcompound 10 using an anhydrous acid (e.g., HCl in dioxane, TFA) producesthe free amine. If desired, reductive amination of the amine (using analdehyde and reducing agent (e.g., NaBH(OAc)₃)), or alkylation understandard conditions allows the preparation of the compound 11.

Scheme 4 shows a general scheme for the synthesis of compound 14,wherein R², R³, R⁵, R⁶, R^(6a), R⁷, A and p are as defined herein,R^(1c) is alkyl, cycloalkyl, aryl or heteroaryl, and PG is a protectinggroup, such as Boc, CBz, benzyl, or R⁴ as defined herein. Compound 9a,wherein R^(1a) is as defined herein, can be converted to compound 12 byreaction with an appropriately substituted amine under standard S_(N)Arreaction conditions. Compound 12 may be protected with standardN-protecting groups (such as tert-butoxycarbonyl, p-methoxybenzyl, etc.)to give compound 13, wherein PG is a protecting group. Compound 14 maythen be prepared using an appropriate coupling reaction (such as, butnot limited to, a Suzuki, Ullman or Negishi coupling). Compound 14 maythen be deprotected with a strong acid (e.g., HCl, trifluoroacetic acid(“TFA”), etc.) to give compound 15.

Scheme 5 shows a general method for the synthesis of compound 18,wherein R², R³, R⁵, R⁶, R^(6a), R⁷, A and p are as defined herein andR^(1d) is hydrogen or a thioether (e.g., —S(C₁-C₆ alkyl)). Compound 16,wherein PG is a protecting group, such as Boc, CBz, benzyl, or R⁴ asdefined herein, may be functionalized to install R^(1d) viadeprotonation under standard conditions (e.g., MeLi in an appropriatesolvent such as tetrahydrofuran), followed by lithiation under standardconditions (e.g., n-BuLi in an appropriate solvent such astetrahydrofuran) and trapping with a suitable electrophile such as, butnot limited to, a disulfide or ammonium chloride to give compound 17.Compound 17 may then be deprotected with a strong acid (e.g., HCl, TFA,etc.) to give compound 18.

In another embodiment of the present invention, a process for preparingcompounds of Formula I (or 10, 11, 15 or 18) is provided, comprising:

(a) reacting a compound of Formula 9:

wherein R^(1b) is halogen or CF₃; and R² is selected from C₁-C₆ alkyl, asaturated or partially unsaturated C₃-C₆ cycloalkyl, phenyl, a saturatedor partially unsaturated 5 or 6 membered heterocyclic, a 5 or 6 memberedheteroaryl, an 8 to 10 membered bicyclic aryl, an 8 to 10 memberedbicyclic heterocyclic, and an 8 to 10 membered bicyclic heteroaryl,wherein the alkyl, cycloalkyl, phenyl, heterocyclics, heteroaryls andaryl are optionally substituted with one or more groups selected fromOH, CN, halogen, oxo (except not on phenyl, aryl or heteroaryl), CF₃,C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), and NR^(e)R^(f); andR^(e) and R^(f) are independently selected from hydrogen and C₁-C₃alkyl;

with an appropriately substituted amine having the formula:

wherein A is selected from a direct bond or CR^(a)R^(b); R³ is selectedfrom hydrogen or C₁-C₄ alkyl optionally substituted with OH, F or C₃-C₆cycloalkyl; R⁵ is selected from hydrogen and CH₃, or A is CR^(a)R^(b),R^(a) and R^(b) are hydrogen, and R³ and R⁵ together with the atoms towhich they are attached form a 5 or 6 membered ring; R⁶ is selected fromhydrogen, F, OH, —OCH₃ and C₁-C₃ alkyl, or A is a direct bond, R^(6a) ishydrogen and R³ and R⁶ together with the atoms to which they areattached form a 5 or 6 membered ring; R^(6a) is selected from hydrogen,F, OH and CH₃; R⁷ is hydrogen, or A is CR^(a)R^(b) and R³ and R⁷together with the atoms to which they are attached form a 5 or 6membered ring; R^(a) is hydrogen, or R⁴ and R^(b) are absent and R³ andR^(a) together with the atoms to which they are attached form anaromatic 5 or 6 membered ring; R^(b) is hydrogen or absent; p is 0, 1, 2or 3; and PG is a protecting group (such as Boc, CBz, benzyl, or R⁴,wherein R⁴ is selected from hydrogen or C₁-C₄ alkyl optionallysubstituted with OH, F or C₃-C₆ cycloalkyl, or R³ and R⁴ together withthe atoms to which they are attached form a 5 or 6 membered ring);

under standard S_(N)Ar reaction conditions to prepare a compound ofFormula 10:

(b) alkylating a compound of Formula 10:

wherein R^(1b) is halogen or CF₃; R² is selected from C₁-C₆ alkyl, asaturated or partially unsaturated C₃-C₆ cycloalkyl, phenyl, a saturatedor partially unsaturated 5 or 6 membered heterocyclic, a 5 or 6 memberedheteroaryl, an 8 to 10 membered bicyclic aryl, an 8 to 10 memberedbicyclic heterocyclic, and an 8 to 10 membered bicyclic heteroaryl,wherein the alkyl, cycloalkyl, phenyl, heterocyclics, heteroaryls andaryl are optionally substituted with one or more groups selected fromOH, CN, halogen, oxo (except not on phenyl, aryl or heteroaryl), CF₃,C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), and NR^(e)R^(f); R^(e)and R^(f) are independently selected from hydrogen and C₁-C₃ alkyl; A isselected from a direct bond or CR^(a)R^(b); R³ is selected from hydrogenor C₁-C₄ alkyl optionally substituted with OH, F or C₃-C₆ cycloalkyl; R⁵is selected from hydrogen and CH₃, or A is CR^(a)R^(b), R^(a) and R^(b)are hydrogen, and R³ and R⁵ together with the atoms to which they areattached form a 5 or 6 membered ring; R⁶ is selected from hydrogen, F,OH, —OCH₃ and C₁-C₃ alkyl, or A is a direct bond, R^(6a) is hydrogen andR³ and R⁶ together with the atoms to which they are attached form a 5 or6 membered ring; R^(6a) is selected from hydrogen, F, OH and CH₃; R⁷ ishydrogen, or A is CR^(a)R^(b) and R³ and R⁷ together with the atoms towhich they are attached form a 5 or 6 membered ring; R^(a) is hydrogen,or R⁴ and R^(b) are absent and R³ and R^(a) together with the atoms towhich they are attached form an aromatic 5 or 6 membered ring; R^(b) ishydrogen or absent; and p is 0, 1, 2 or 3;

to provide a compound of Formula 11:

wherein R^(4a) is C₁-C₄ alkyl;

(c) protecting a compound of Formula 12:

wherein R^(1a) is halogen; R² is selected from C₁-C₆ alkyl, a saturatedor partially unsaturated C₃-C₆ cycloalkyl, phenyl, a saturated orpartially unsaturated 5 or 6 membered heterocyclic, a 5 or 6 memberedheteroaryl, an 8 to 10 membered bicyclic aryl, an 8 to 10 memberedbicyclic heterocyclic, and an 8 to 10 membered bicyclic heteroaryl,wherein the alkyl, cycloalkyl, phenyl, heterocyclics, heteroaryls andaryl are optionally substituted with one or more groups selected fromOH, CN, halogen, oxo (except not on phenyl, aryl or heteroaryl), CF₃,C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), and NR^(e)R^(f); R^(e)and R^(f) are independently selected from hydrogen and C₁-C₃ alkyl; A isselected from a direct bond or CR^(a)R^(b); R³ is selected from hydrogenor C₁-C₄ alkyl optionally substituted with OH, F or C₃-C₆ cycloalkyl; R⁵is selected from hydrogen and CH₃, or A is CR^(a)R^(b), R^(a) and R^(b)are hydrogen, and R³ and R⁵ together with the atoms to which they areattached form a 5 or 6 membered ring; R⁶ is selected from hydrogen, F,OH, —OCH₃ and C₁-C₃ alkyl, or A is a direct bond, R^(6a) is hydrogen andR³ and R⁶ together with the atoms to which they are attached form a 5membered ring; R^(6a) is selected from hydrogen, F, OH and CH₃; R⁷ ishydrogen, or A is CR^(a)R^(b) and R³ and R⁷ together with the atoms towhich they are attached form a 5 or 6 membered ring; R^(a) is hydrogen,or R⁴ and R^(b) are absent and R³ and R^(a) together with the atoms towhich they are attached form an aromatic 5 or 6 membered ring; R^(b) ishydrogen or absent; p is 0, 1, 2 or 3; and PG is a protecting group(such as tert-butoxycarbonyl, or p-methoxybenzyl);

performing a coupling reaction; and

deprotecting the compound to provide a compound of Formula 15:

wherein R^(1c) is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl or a 5 or 6membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl or heteroarylare optionally substituted with one or more groups selected fromhalogen, CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d); and

(d) functionalizing a compound of Formula 16:

wherein R² is selected from C₁-C₆ alkyl, a saturated or partiallyunsaturated C₃-C₆ cycloalkyl, phenyl, a saturated or partiallyunsaturated 5 or 6 membered heterocyclic, a 5 or 6 membered heteroaryl,an 8 to 10 membered bicyclic aryl, an 8 to 10 membered bicyclicheterocyclic, and an 8 to 10 membered bicyclic heteroaryl, wherein thealkyl, cycloalkyl, phenyl, heterocyclics, heteroaryls and aryl areoptionally substituted with one or more groups selected from OH, CN,halogen, oxo (except not on phenyl, aryl or heteroaryl), CF₃, C₁-C₆alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), and NR^(e)R^(f); R^(e) andR^(f) are independently selected from hydrogen and C₁-C₃ alkyl; A isselected from a direct bond or CR^(a)R^(b); R³ is selected from hydrogenor C₁-C₄ alkyl optionally substituted with OH, F or C₃-C₆ cycloalkyl; R⁵is selected from hydrogen and CH₃, or A is CR^(a)R^(b), R^(a) and R^(b)are hydrogen, and R³ and R⁵ together with the atoms to which they areattached form a 5 or 6 membered ring; R⁶ is selected from hydrogen, F,OH, —OCH₃ and C₁-C₃ alkyl, or A is a direct bond, R^(6a) is hydrogen andR³ and R⁶ together with the atoms to which they are attached form a 5membered ring; R^(6a) is selected from hydrogen, F, OH and CH₃; R⁷ ishydrogen, or A is CR^(a)R^(b) and R³ and R⁷ together with the atoms towhich they are attached form a 5 or 6 membered ring; R^(a) is hydrogen,or R⁴ and R^(b) are absent and R³ and R^(a) together with the atoms towhich they are attached form an aromatic 5 or 6 membered ring; R^(b) ishydrogen or absent; p is 0, 1, 2 or 3; PG is a protecting group, such asBoc, CBz, benzyl, or R⁴; and R⁴ is selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F or C₃-C₆ cycloalkyl, or R³ and R⁴together with the atoms to which they are attached form a 5 or 6membered ring; followed by deprotection to provide a compound of Formula18:

wherein R^(1d) is hydrogen or —S(C₁-C₆ alkyl).

In another embodiment of the present invention, a process for preparingcompounds of Formula I (or 10, 11, 15 or 18) is provided, comprising:

(a) reacting a compound of Formula 9:

wherein R^(1b) is halogen, CF₃, and —O(C₁-C₆ alkyl), wherein the alkylmay be optionally substituted with one or more groups selected fromhalogen, CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d); R² isselected from C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), asaturated or partially unsaturated C₃-C₆ cycloalkyl, phenyl, a saturatedor partially unsaturated 4 to 6 membered heterocyclic, a 5 or 6 memberedheteroaryl, an 8 to 10 membered bicyclic aryl, an 8 to 10 memberedbicyclic heterocyclic, and an 8 to 10 membered bicyclic heteroaryl,wherein the alkyls, cycloalkyl, phenyl, heterocyclics, heteroaryls andaryl are optionally substituted with one or more groups selected fromOH, CN, halogen, oxo (except not on phenyl, aryl or heteroaryl), CF₃,cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl),—S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl, wherein the phenyl isoptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h); R^(c) andR^(d) are independently selected from hydrogen and C₁-C₃ alkyl, or R^(c)and R^(d) together with the atom to which they are attached form a 5 or6 membered ring; R^(e) and R^(f) are independently selected fromhydrogen and C₁-C₃ alkyl; R^(g) and R^(h) are independently selectedfrom hydrogen and C₁-C₃ alkyl; and R^(i) is C₁-C₃ alkyl;

with an appropriately substituted amine having the formula:

wherein A is selected from a direct bond or CR^(a)R^(b); R³ is selectedfrom hydrogen or C₁-C₄ alkyl optionally substituted with OH, F, —O(C₁-C₃alkyl) or C₃-C₆ cycloalkyl; R⁵ is selected from hydrogen and CH₃, or Ais CR^(a)R^(b), R^(a) and R^(b) are hydrogen, and R³ and R⁵ togetherwith the atoms to which they are attached form a 5 or 6 membered ring;R⁶ is selected from hydrogen, F, OH, —OCH₃, C₁-C₃ alkyl and cyclopropyl,or A is a direct bond, R^(6a) is hydrogen and R³ and R⁶ together withthe atoms to which they are attached form a 5 or 6 membered ring; R^(6a)is selected from hydrogen, F, OH and CH₃; R⁷ is hydrogen, or A isCR^(a)R^(b) and R³ and R⁷ together with the atoms to which they areattached form a 5 or 6 membered ring; R^(a) is hydrogen, or R⁴ and R^(b)are absent and R³ and R^(a) together with the atoms to which they areattached form an aromatic 5 or 6 membered ring; R^(b) is hydrogen orabsent; p is 0, 1, 2 or 3; and PG is a protecting group (such as Boc,CBz, benzyl, or R⁴, wherein R⁴ is selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F, —O(C₁-C₃ alkyl) or C₃-C₆ cycloalkyl,or R³ and R⁴ together with the atoms to which they are attached form a 5or 6 membered ring);

under standard S_(N)Ar reaction conditions to prepare a compound ofFormula 10:

(b) alkylating a compound of Formula 10:

wherein R^(1b) is halogen, CF₃, —O(C₁-C₆ alkyl), wherein the alkyl maybe optionally substituted with one or more groups selected from halogen,CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d); R² is selectedfrom C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), a saturated orpartially unsaturated C₃-C₆ cycloalkyl, phenyl, a saturated or partiallyunsaturated 4 to 6 membered heterocyclic, a 5 or 6 membered heteroaryl,an 8 to 10 membered bicyclic aryl, an 8 to 10 membered bicyclicheterocyclic, and an 8 to 10 membered bicyclic heteroaryl, wherein thealkyls, cycloalkyl, phenyl, heterocyclics, heteroaryls and aryl areoptionally substituted with one or more groups selected from OH, CN,halogen, oxo (except not on phenyl, aryl or heteroaryl), CF₃,cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl),—S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl, wherein the phenyl isoptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h); R^(c) andR^(d) are independently selected from hydrogen and C₁-C₃ alkyl, or R^(c)and R^(d) together with the atom to which they are attached form a 5 or6 membered ring; R^(e) and R^(f) are independently selected fromhydrogen and C₁-C₃ alkyl; R^(g) and R^(h) are independently selectedfrom hydrogen and C₁-C₃ alkyl; R^(i) is C₁-C₃ alkyl; A is selected froma direct bond or CR^(a)R^(b); R³ is selected from hydrogen or C₁-C₄alkyl optionally substituted with OH, F, —O(C₁-C₃ alkyl) or C₃-C₆cycloalkyl; R⁵ is selected from hydrogen and CH₃, or A is CR^(a)R^(b),R^(a) and R^(b) are hydrogen, and R³ and R⁵ together with the atoms towhich they are attached form a 5 or 6 membered ring; R⁶ is selected fromhydrogen, F, OH, —OCH₃, C₁-C₃ alkyl and cyclopropyl, or A is a directbond, R^(6a) is hydrogen and R³ and R⁶ together with the atoms to whichthey are attached form a 5 or 6 membered ring; R^(6a) is selected fromhydrogen, F, OH and CH₃; R⁷ is hydrogen, or A is CR^(a)R^(b) and R³ andR⁷ together with the atoms to which they are attached form a 5 or 6membered ring; R^(a) is hydrogen, or R⁴ and R^(b) are absent and R³ andR^(a) together with the atoms to which they are attached form anaromatic 5 or 6 membered ring; R^(b) is hydrogen or absent; and p is 0,1, 2 or 3;

to provide a compound of Formula 11:

wherein R^(4a) is C₁-C₄ alkyl;

(c) protecting a compound of Formula 12:

wherein R^(1a) is halogen or OH; R² is selected from C₁-C₆ alkyl,—O(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), a saturated or partially unsaturatedC₃-C₆ cycloalkyl, phenyl, a saturated or partially unsaturated 4 to 6membered heterocyclic, a 5 or 6 membered heteroaryl, an 8 to 10 memberedbicyclic aryl, an 8 to 10 membered bicyclic heterocyclic, and an 8 to 10membered bicyclic heteroaryl, wherein the alkyls, cycloalkyl, phenyl,heterocyclics, heteroaryls and aryl are optionally substituted with oneor more groups selected from OH, CN, halogen, oxo (except not on phenyl,aryl or heteroaryl), CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i),C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl,wherein the phenyl is optionally substituted with one or more groupsselected from OH, CN, halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), andNR^(g)R^(h); R^(e) and R^(f) are independently selected from hydrogenand C₁-C₃ alkyl; R^(g) and R^(h) are independently selected fromhydrogen and C₁-C₃ alkyl; R^(i) is C₁-C₃ alkyl; A is selected from adirect bond or CR^(a)R^(b); R³ is selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F, —O(C₁-C₃ alkyl) or C₃-C₆ cycloalkyl;R⁵ is selected from hydrogen and CH₃, or A is CR^(a)R^(b), R^(a) andR^(b) are hydrogen, and R³ and R⁵ together with the atoms to which theyare attached form a 5 or 6 membered ring; R⁶ is selected from hydrogen,F, OH, —OCH₃, C₁-C₃ alkyl and cyclopropyl, or A is a direct bond, R^(6a)is hydrogen and R³ and R⁶ together with the atoms to which they areattached form a 5 membered ring; R^(6a) is selected from hydrogen, F, OHand CH₃; R⁷ is hydrogen, or A is CR^(a)R^(b) and R³ and R⁷ together withthe atoms to which they are attached form a 5 or 6 membered ring; R^(a)is hydrogen, or R⁴ and R^(b) are absent and R³ and R^(a) together withthe atoms to which they are attached form an aromatic 5 or 6 memberedring; R^(b) is hydrogen or absent; p is 0, 1, 2 or 3; and PG is aprotecting group (such as tert-butoxycarbonyl, or p-methoxybenzyl);

performing a coupling reaction; and

deprotecting the compound to provide a compound of Formula 15:

wherein R^(1c) is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, phenyl or a 5 or 6membered heteroaryl, wherein the alkyl, cycloalkyl, phenyl or heteroarylare optionally substituted with one or more groups selected fromhalogen, CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) and NR^(c)R^(d); andR^(c) and R^(d) are independently selected from hydrogen and C₁-C₃alkyl, or R^(c) and R^(d) together with the atom to which they areattached form a 5 or 6 membered ring; and

(d) functionalizing a compound of Formula 16:

wherein R² is selected from C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —NH(C₁-C₆alkyl), a saturated or partially unsaturated C₃-C₆ cycloalkyl, phenyl, asaturated or partially unsaturated 4 to 6 membered heterocyclic, a 5 or6 membered heteroaryl, an 8 to 10 membered bicyclic aryl, an 8 to 10membered bicyclic heterocyclic, and an 8 to 10 membered bicyclicheteroaryl, wherein the alkyls, cycloalkyl, phenyl, heterocyclics,heteroaryls and aryl are optionally substituted with one or more groupsselected from OH, CN, halogen, oxo (except not on phenyl, aryl orheteroaryl), CF₃, cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl), NR^(e)R^(f) and phenyl, whereinthe phenyl is optionally substituted with one or more groups selectedfrom OH, CN, halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), andNR^(g)R^(h); R^(e) and R^(f) are independently selected from hydrogenand C₁-C₃ alkyl; R^(g) and R^(h) are independently selected fromhydrogen and C₁-C₃ alkyl; R^(i) is C₁-C₃ alkyl; A is selected from adirect bond or CR^(a)R^(b); R³ is selected from hydrogen or C₁-C₄ alkyloptionally substituted with OH, F, —O(C₁-C₃ alkyl) or C₃-C₆ cycloalkyl;R⁵ is selected from hydrogen and CH₃, or A is CR^(a)R^(b), R^(a) andR^(b) are hydrogen, and R³ and R⁵ together with the atoms to which theyare attached form a 5 or 6 membered ring; R⁶ is selected from hydrogen,F, OH, —OCH₃, C₁-C₃ alkyl and cyclopropyl, or A is a direct bond, R^(6a)is hydrogen and R³ and R⁶ together with the atoms to which they areattached form a 5 membered ring; R^(6a) is selected from hydrogen, F, OHand CH₃; R⁷ is hydrogen, or A is CR^(a)R^(b) and R³ and R⁷ together withthe atoms to which they are attached form a 5 or 6 membered ring; R^(a)is hydrogen, or R⁴ and R^(b) are absent and R³ and R^(a) together withthe atoms to which they are attached form an aromatic 5 or 6 memberedring; R^(b) is hydrogen or absent; p is 0, 1, 2 or 3; PG is a protectinggroup, such as Boc, CBz, benzyl, or R⁴; and R⁴ is selected from hydrogenor C₁-C₄ alkyl optionally substituted with OH, F, —O(C₁-C₃ alkyl) orC₃-C₆ cycloalkyl, or R³ and R⁴ together with the atoms to which they areattached form a 5 or 6 membered ring;

followed by deprotection to provide a compound of Formula 18:

wherein R^(1d) is hydrogen or —S(C₁-C₆ alkyl).

In preparing compounds of Formula I, protection of remotefunctionalities (e.g., primary or secondary amines, etc.) ofintermediates may be necessary. The need for such protection will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. Suitable amino-protecting groups (NH-Pg)include acetyl, trifluoroacetyl, t-butyloxycarbonyl (“Boc”),benzyloxycarbonyl (“CBz”) and 9-fluorenylmethyleneoxycarbonyl (“Fmoc”).The need for such protection is readily determined by one skilled in theart. For a general description of protecting groups and their use, seeT. W. Greene, et al. Greene's Protective Groups in Organic Synthesis.New York: Wiley Interscience, 2006.

Methods of Separation

It may be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified (hereinafter separated) tothe desired degree of homogeneity by the techniques common in the art.Typically such separations involve multiphase extraction,crystallization from a solvent or solvent mixture, distillation,sublimation, or chromatography. Chromatography can involve any number ofmethods including, for example: reverse-phase and normal phase; sizeexclusion; ion exchange; high, medium and low pressure liquidchromatography methods and apparatus; small scale analytical; simulatedmoving bed (SMB) and preparative thin or thick layer chromatography, aswell as techniques of small scale thin layer and flash chromatography.One skilled in the art will apply techniques most likely to achieve thedesired separation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers.Enantiomers can also be separated by use of a chiral HPLC column.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. Stereochemistry of OrganicCompounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H.,et al. “Chromatographic resolution of enantiomers: Selective review.” J.Chromatogr., 113(3) (1975): pp. 283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: Wainer,Irving W., Ed. Drug Stereochemistry: Analytical Methods andPharmacology. New York: Marcel Dekker, Inc., 1993.

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York:John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can beformed by reacting asymmetric compounds with enantiomerically purechiral derivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−) menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III, Peyton.“Resolution of (±)-5-Bromonornicotine. Synthesis of (R)- and(S)-Nornicotine of High Enantiomeric Purity.” J. Org. Chem. Vol. 47, No.21 (1982): pp. 4165-4167), of the racemic mixture, and analyzing the ¹HNMR spectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111).

By method (3), a racemic mixture of two enantiomers can be separated bychromatography using a chiral stationary phase (Lough, W. J., Ed. ChiralLiquid Chromatography. New York: Chapman and Hall, 1989; Okamoto,Yoshio, et al. “Optical resolution of dihydropyridine enantiomers byhigh-performance liquid chromatography using phenylcarbamates ofpolysaccharides as a chiral stationary phase.” J. of Chromatogr. Vol.513 (1990) 375-378). Enriched or purified enantiomers can bedistinguished by methods used to distinguish other chiral molecules withasymmetric carbon atoms, such as optical rotation and circulardichroism.

Administration and Pharmaceutical Formulations

The compounds of the invention may be administered by any convenientroute appropriate to the condition to be treated. Suitable routesinclude oral, parenteral (including subcutaneous, intramuscular,intravenous, intraarterial, intradermal, intrathecal and epidural),transdermal, rectal, nasal, topical (including buccal and sublingual),vaginal, intraperitoneal, intrapulmonary and intranasal.

The compounds may be administered in any convenient administrative form,e.g., tablets, powders, capsules, solutions, dispersions, suspensions,syrups, sprays, suppositories, gels, emulsions, patches, etc. Suchcompositions may contain components conventional in pharmaceuticalpreparations, e.g., diluents, carriers, pH modifiers, sweeteners,bulking agents, and further active agents. If parenteral administrationis desired, the compositions will be sterile and in a solution orsuspension form suitable for injection or infusion.

A typical formulation is prepared by mixing a compound of the presentinvention and a carrier or excipient. Suitable carriers and excipientsare well known to those skilled in the art and are described in detailin, e.g., Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Formsand Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins,2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice ofPharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe,Raymond C. Handbook of Pharmaceutical Excipients. Chicago,Pharmaceutical Press, 2005. The formulations may also include one ormore buffers, stabilizing agents, surfactants, wetting agents,lubricating agents, emulsifiers, suspending agents, preservatives,antioxidants, opaquing agents, glidants, processing aids, colorants,sweeteners, perfuming agents, flavoring agents, diluents and other knownadditives to provide an elegant presentation of the drug (i.e., acompound of the present invention or pharmaceutical composition thereof)or aid in the manufacturing of the pharmaceutical product (i.e.,medicament).

One embodiment of the present invention includes a pharmaceuticalcomposition comprising a compound of Formula I, or a stereoisomer orpharmaceutically acceptable salt thereof. In a further embodiment, thepresent invention provides a pharmaceutical composition comprising acompound of Formula I, or a stereoisomer or pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable carrier orexcipient.

Methods of Treatment with Compounds of the Invention

The invention includes methods of treating or preventing disease orcondition by administering one or more compounds of this invention, or astereoisomer or pharmaceutically acceptable salt thereof. In oneembodiment, a human patient is treated with a compound of the presentinvention, or a stereoisomer or pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier, adjuvant, or vehiclein an amount to detectably inhibit CHK1 activity.

In another embodiment of the present invention, a method of preventingor treating a disease or disorder modulated by CHK1 and/or CHK2,comprising administering to a mammal in need of such treatment aneffective amount of a compound of the present invention is provided.

In another embodiment of the present invention, a method of treating ahyperproliferative disease in a mammal comprising administering atherapeutically effective amount of the compound of the presentinvention, or a stereoisomer or pharmaceutically acceptable saltthereof, to the mammal is provided.

In another embodiment, a method of treating or preventing cancer,including the below identified conditions, in a mammal in need of suchtreatment, wherein the method comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a stereoisomer or pharmaceutically acceptable salt thereof.

In certain embodiments, the CHK1 inhibitor of the present invention(i.e., a compound of Formula I) is administered in combination with aDNA damaging agent. Generally, the DNA damaging agent will beadministered before the CHK1 inhibitor of the present invention. DNAdamaging agents include Gemzar® (gemcitabine), Camptosar® (irinotecan orCPT-11), Temodar® (temozolomide), Xeloda® (capecitabine), Hycamtin®(topotecan), cisplatin, Eloxatin® (oxaliplatin), Paraplatin®(carboplatin), camptothecin, ara-C (cytarabine), 5-FU (fluorouracil),Cytoxan® (cyclophosphamide), Etopophos® or Vepesid® (etoposidephosphate), Vumon® (teniposide), Adriamycin PFS® or Adriamycin RDF®(doxorubicin), daunorubicin, Alimta® (pemetrexed), and radiation. Incertain embodiments, the DNA damaging agent is selected from the groupconsisting of gemcitabine, irinotecan, temozolomide, capecitabine,camptothecin, cisplatin, ara-C, and 5-FU. In certain embodiments, theDNA damaging agent is selected from gemcitabine, irinotecan,temozolomide and capecitabine. In certain embodiments, the DNA damagingagent is selected from gemcitabine, irinotecan, cisplatin, oxaliplatin,carboplatin and cytarabine. In certain embodiments, the DNA damagingagent is selected from gemcitabine and irinotecan. The DNA damagingagent is administered at its approved or recommended dose.

Because of the ability of a CHK1 inhibitor to potentiate the activity ofmany anti-cancer agents it is expected that a wide range of tumor typesmay be treated by the compositions and methods of the invention. Theseconditions include, but are not limited to: Cardiac: sarcoma(angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma,rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma(squamous cell, undifferentiated small cell, undifferentiated largecell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenicsarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma and giant celltumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma,osteitis deformans), meninges (meningioma, meningiosarcoma,gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma,germinoma [pinealoma], glioblastoma multiform, oligodendroglioma,schwannoma, retinoblastoma, congenital tumors), spinal cordneurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma],fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acuteand chronic], acute lymphoblastic leukemia, chronic lymphocyticleukemia, myeloproliferative diseases, multiple myeloma, myelodysplasticsyndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignantlymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cellcarcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; Breast: invasive breast carcinomas(invasive ductal carcinoma and invasive lobular carcinoma), etc.; andAdrenal glands: neuroblastoma. The term hyperproliferative diseaseincludes the above identified conditions. The term “cancerous cell” asprovided herein, includes a cell afflicted by any one of the aboveidentified conditions.

In certain embodiments of the present invention, the cancer is selectedfrom colorectal cancer (including Ras mutations), small cell lungcancer, non-small cell lung cancer, glioma, ovarian cancer, metastaticbreast cancer, pancreatic cancer, hepatobiliary cancer (includinghepatocellular cancer, bile duct cancer and cholangiocarcinoma), gastriccancer, testicular cancer, head and neck squamous cell carcinoma,leukemia (including acute myeloid leukemia, acute lymphoblasticleukemia, chronic myeloid leukemia, and chronic lymphoid leukemia),lymphoma (including mantle cell lymphoma, Hodgkin's lymphoma andnon-Hodgkin's lymphoma), and prostrate cancer.

In certain embodiments of the present invention, the cancer is a solidtumor cancer.

In certain embodiments of the present invention, the cancer is selectedfrom pancreatic cancer, ovarian cancer and colorectal cancer.

In certain embodiments of the present invention, the cancer is selectedfrom colorectal cancer (including Ras mutations), small cell lungcancer, non-small cell lung cancer, and glioma. In certain embodiments,the CHK1 inhibitor is administered in combination with a DNA damagingagent. In a further embodiment, the DNA damaging agent is irinotecan.

In certain embodiments of the present invention, the cancer is selectedfrom non-small cell lung cancer, ovarian cancer, metastatic breastcancer, pancreatic cancer, hepatobiliary cancer (includinghepatocellular cancer, bile duct cancer and cholangiocarcinoma), andgastric cancer. In certain embodiments, the CHK1 inhibitor isadministered in combination with a DNA damaging agent. In a furtherembodiment, the DNA damaging agent is gemcitabine.

In certain embodiments of the present invention, the cancer is selectedfrom colorectal cancer (including Ras mutations), small cell lungcancer, non-small cell lung cancer, ovarian cancer, hepatobiliary cancer(including hepatocellular cancer, bile duct cancer andcholangiocarcinoma), gastric cancer, testicular cancer, and head andneck squamous cell carcinoma. In certain embodiments, the CHK1 inhibitoris administered in combination with a DNA damaging agent. In a furtherembodiment, the DNA damaging agent is selected from the group consistingof cisplatin, oxaliplatin, and carboplatin.

In certain embodiments of the present invention, the cancer is selectedfrom leukemia (including acute myeloid leukemia, acute lymphoblasticleukemia, chronic myeloid leukemia, and chronic lymphoid leukemia),lymphoma (including mantle cell lymphoma, Hodgkin's lymphoma andnon-Hodgkin's lymphoma), and prostrate cancer. In certain embodiments,the CHK1 inhibitor is administered in combination with a DNA damagingagent. In a further embodiment, the DNA damaging agent is cytarabine.

Another embodiment of the present invention provides the use of acompound of the present invention, or a stereoisomer or pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for thetreatment of cancer.

In another embodiment, a method of treating or preventing a disease ordisorder modulated by CHK1 and/or CHK2, comprising administering to amammal in need of such treatment an effective amount of a compound ofthe present invention, or a stereoisomer or pharmaceutically acceptablesalt thereof.

In another embodiment, a method of preventing or treating cancer,comprising administering to a mammal in need of such treatment aneffective amount of a compound of the present invention, alone or incombination with one or more additional compounds having anti-cancerproperties.

CHK1 inhibitors are expected to potentiate the activity of a wide rangeof anti-cancer agents (or DNA damaging agents), when such agent(s)trigger the CHK1 dependent cell cycle checkpoint.

The invention relates to a composition for the treatment of ahyperproliferative disease in a mammal, comprising a therapeuticallyeffective amount of a compound of the present invention, or astereoisomer or a pharmaceutically acceptable salt thereof, incombination with an anti-tumor agent selected from mitotic inhibitors,alkylating agents, anti-metabolites, antisense DNA or RNA, intercalatingantibiotics, growth factor inhibitors, signal transduction inhibitors,cell cycle inhibitors, enzyme inhibitors, retinoid receptor modulators,proteasome inhibitors, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, anti-androgens,targeted antibodies, HMG-CoA reductase inhibitors, and prenyl-proteintransferase inhibitors.

The invention also relates to a method for the treatment of ahyperproliferative disorder in a mammal that comprises administering tosaid mammal a therapeutically effective amount of a compound of thepresent invention, or a stereoisomer or a pharmaceutically acceptablesalt thereof, in combination with an anti-tumor agent selected frommitotic inhibitors, alkylating agents, anti-metabolites, antisense DNAor RNA, intercalating antibiotics, growth factor inhibitors, signaltransduction inhibitors, cell cycle inhibitors, enzyme inhibitors,retinoid receptor modulators, proteasome inhibitors, topoisomeraseinhibitors, biological response modifiers, anti-hormones, angiogenesisinhibitors, anti-androgens, targeted antibodies, HMG-CoA reductaseinhibitors, and prenyl-protein transferase inhibitors.

Another embodiment provides the compounds of the present invention foruse in therapy. In a further embodiment, the use also includes the useof a DNA damaging agent.

Another embodiment provides the compounds of the present invention foruse in the treatment of a hyperproliferative disease. In a furtherembodiment, the hyperproliferative disease is cancer, including theabove identified conditions. In a further embodiment, the use alsoincludes the use of a DNA damaging agent.

This invention also relates to a pharmaceutical composition forinhibiting abnormal cell growth in a mammal which comprises an amount ofa compound of the present invention, or a stereoisomer or apharmaceutically acceptable salt thereof, in combination with an amountof a chemotherapeutic, wherein the amounts of the compound, stereoisomeror salt and of the chemotherapeutic are together effective in inhibitingabnormal cell growth. Many chemotherapeutics are known in the art. Incertain embodiments, the chemotherapeutic is selected from mitoticinhibitors, alkylating agents, anti-metabolites, antisense DNA or RNA,intercalating antibiotics, growth factor inhibitors, signal transductioninhibitors, cell cycle inhibitors, enzyme inhibitors, retinoid receptormodulators, proteasome inhibitors, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, angiogenesis inhibitors,anti-androgens, targeted antibodies, HMG-CoA reductase inhibitors,and/or prenyl-protein transferase inhibitors.

This invention relates to a method for inhibiting abnormal cell growthin a mammal or treating a hyperproliferative disorder in which themethod comprises administering to the mammal an amount of a compound ofthe present invention, or a stereoisomer or a pharmaceuticallyacceptable salt thereof, in combination with radiation therapy, whereinthe amounts of the compound or salt, in combination with the radiationtherapy is effective in inhibiting abnormal cell growth or treating thehyperproliferative disorder in the mammal. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of thecompound of the invention in this combination therapy can be determinedas described herein.

It is believed that the compounds of the present invention can renderabnormal cells more sensitive to treatment with radiation for purposesof killing and/or inhibiting the growth of such cells. Accordingly, thisinvention further relates to a method for sensitizing abnormal cells ina mammal to treatment with radiation, which comprises administering tothe mammal an amount of a compound of the present invention or astereoisomer or a pharmaceutically acceptable salt thereof, which amountis effective in sensitizing abnormal cells to radiation treatment. Theamount of the compound, stereoisomer or salt to be used in this methodcan be determined according to means for ascertaining effective amountsof such compounds as described herein or by methods know to thoseskilled in the art.

Another embodiment of the present invention provides the use of acompound of the present invention, or a stereoisomer or pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for thetreatment of hyperproliferative diseases. In a further embodiment, thehyperproliferative disease may be cancer, including the above identifiedconditions. In a further embodiment, the use also includes the use of aDNA damaging agent.

In another embodiment of the present invention, use of a compound of thepresent invention, in the manufacture of a medicament, for use as a CHK1and/or CHK2 inhibitor in the treatment of a patient undergoing cancertherapy, including the above identified conditions, is provided. In afurther embodiment, the use also includes the use of a DNA damagingagent.

Another embodiment of the present invention provides the use of acompound of the present invention in the treatment of ahyperproliferative disease. In a further embodiment, thehyperproliferative disease is cancer, including the above identifiedconditions. In a further embodiment, the use also includes the use of aDNA damaging agent.

Another embodiment provides the use of a compound of the presentinvention in the manufacture of a medicament, for use as a CHK1 and/orCHK2 inhibitor in the treatment of a patient undergoing cancer therapy.In a further embodiment, the use also includes the use of a DNA damagingagent.

In another embodiment, a pharmaceutical composition comprising acompound of the present invention for use in the treatment of ahyperproliferative disease is provided.

In another embodiment, a pharmaceutical composition comprising acompound of the present invention for use in the treatment of cancer isprovided.

Combination Therapy

The compounds of this invention and stereoisomers and pharmaceuticallyacceptable salts thereof may be employed alone or in combination withother therapeutic agents for treatment. The compounds of the presentinvention can be used in combination with one or more additional drugs,for example an anti-inflammatory compound that works by a differentmechanism of action. The second compound of the pharmaceuticalcombination formulation or dosing regimen preferably has complementaryactivities to the compound of this invention such that they do notadversely affect each other. Such molecules are suitably present incombination in amounts that are effective for the purpose intended. Thecompounds may be administered together in a unitary pharmaceuticalcomposition or separately and, when administered separately this mayoccur simultaneously or sequentially in any order. Such sequentialadministration may be close in time or remote in time.

EXAMPLES

In order to illustrate the invention, the following Examples areincluded. However, it is to be understood that these Examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other compounds of the invention, and alternative methods forpreparing the compounds of this invention are deemed to be within thescope of this invention. For example, the synthesis of non-exemplifiedcompounds according to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the Examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Sigma-Aldrich, Alfa Aesar, or TCI, andwere used without further purification unless otherwise indicated.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SepPak cartridge(Waters) (unless otherwise stated). ¹H NMR spectra were recorded on aVarian instrument operating at 400 MHz. ¹H-NMR spectra were obtained asCDCl₃, CD₃OD, D₂O, (CD₃)₂SO, (CD₃)₂CO, C₆D₆, CD₃CN solutions (reportedin ppm), using tetramethylsilane (0.00 ppm) or residual solvent (CDCl₃:7.26 ppm; CD₃OD: 3.31 ppm; D₂O: 4.79 ppm; (CD₃)₂SO: 2.50 ppm; (CD₃)₂CO:2.05 ppm; C₆D₆: 7.16 ppm; CD₃CN: 1.94 ppm) as the reference standard.When peak multiplicities are reported, the following abbreviations areused: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),br (broadened), dd (doublet of doublets), dt (doublet of triplets).Coupling constants, when given, are reported in Hertz (Hz).

Preparative HPLC methods: Some of the final compounds were purified byreverse phase HPLC (0-50% CH₃CN in water) using a Gilson 506C systeminterface, a Gilson 155 UV/VIS detector, a Gilson 215 Nebula liquidhandler/Injector equipped with an 819 injection module, a Gilson 322pump, and a Waters 25 mm×100 mm YMC ODS-AQ Cartridge 120A Part Number:AQ12S111025RC and a Waters PrepLC 25 mm Radial Compression Module.

LCMS methods: Method 1: This method was run on Agilent 1100 instrumentwith a Thermo MSQ with a gradient of 5% to 95% organic gradient (CH₃CN)with a mobile phase of 10 mM ammonium acetate buffer: 1% isopropylalcohol in H₂O. The column used was a YMC ODS-AQ, 3 um, 120 Angstrom4.6×50 mm. This method employed a 4 minute run time, and the instrumentused was Agilent 1100 instrument with a Thermo MSQ.

Method 2: This method was run on Agilent 1100 instrument with a ThermoMSQ with a gradient of 5% to 95% organic gradient (CH₃CN) with a mobilephase of 10 mM ammonium acetate buffer: 1% isopropyl alcohol in H₂O. Thecolumn used was an YMC ODS-AQ, 3 um, 120 Angstrom 4.6×50 mm. This methodemployed a 5.5 minute run time, and the instrument used was Agilent 1100instrument with a Thermo MSQ.

Method 3: This method was run on Thermo Separation Product LC instrumentwith a LCQ Duo M. S and the column, solvents, gradient and the run timewas equal to that of Method 2.

Example A CHK1 Enzymatic Assay

Compounds were diluted in dimethylsulfoxide (“DMSO”) in 3 fold serialdilutions and then added to the reaction to give a final concentrationof 1% DMSO. Compounds were tested in an enzymatic assay using human CHK1kinase domain, amino acids 1 to 273, with 10 additional histidineresidues on the carboxy terminus, purified from bacculovirus. Thesubstrate was the fluorescent Omnia peptide S/T11 from Invitrogen. Theassay contained 25 mM HEPES pH 7.4, 10 mM MgCl₂, 1 mM DTT, 0.01%Triton-X100, 0.5 nM CHK1 enzyme, 2 μM S/T 11 peptide substrate, 60M ATP,test compound, 1% DMSO, in a 25 μL reaction volume. The assay was run atroom temperature in white 384 well polypropylene plates (available fromNunc, Inc of Naperville, Ill.) collecting data every 50 seconds for 45minutes in an Envision plate reader (PerkinElmer, Inc. of Waltham,Mass.), excitation 340 nM, emission 495 nM. The collected data from eachwell was fit to a straight line and the resulting rates were used tocalculate a percent of control. IC₅₀ values for each test compound weredetermined from the percent of control vs. compound concentration plotsusing a four parameter fit.

Examples 1-184 below were tested in the above assay and found to have anIC₅₀ of less than 5 μM. A majority of Examples 1-184 below were testedin the above assay and found to have an IC₅₀ of less than 1 μM.

Example B

tert-Butyl octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

Step A: 1H-Pyrrolo[2,3-c]pyridine (2.50 g, 21.2 mmol) and triethylamine(3.24 mL, 23.3 mmol) were placed in DCM (25 mL) at room temperature.Triethylamine (3.24 mL, 23.3 mmol) was then added, and the reaction wasstirred for 30 minutes. The reaction was then poured into water andextracted with DCM. The organic fraction was dried, filtered, andconcentrated to give the crude product, which was purified by columnchromatography (500:3 DCM:MeOH) to give tert-butyl1H-pyrrolo[2,3-c]pyridine-1-carboxylate (4.4 g, 95% yield).

Step B: tert-Butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.0 g, 4.58mmol) and PtO₂ (0.208 g, 0.916 mmol) were placed in 1:1 EtOH:AcOH (10mL) and hydrogenated at 50 PSI of H₂ for 8 hours (Parr shaker). Thereaction was then concentrated, and the crude oil was dissolved in DCMand poured into saturated Na₂CO₃ and extracted into DCM. The combinedorganic fractions were dried, filtered, and concentrated to givetert-butyl octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.99 g,95% yield) as an oil.

Example C

tert-Butyl 3-methylpiperidin-3-ylcarbamate

Step A: To ethyl piperidine-3-carboxylate (5.0 g, 30.2 mmol) and K₂CO₃(4.2 g, 30.2 mmol) in 1:1 THF-water (100 mL) was added benzylcarbonochloridate (4.5 mL, 31.7 mmol) at 0° C. The reaction mixture wasstirred at room temperature for 2 hours, and then ether (50 mL) wasadded. The organic layer was separated, washed with brine and dried oversodium sulfate. After removal of the solvent, the residue was purifiedby chromatography on silica gel (hexane:ethyl acetate 5:1) to give1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (7.60 g, 86% yield) as anoil.

Step B: To 1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (3.0 g, 10.3mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (12.9mL, 12.9 mmol) in THF at −78° C., and the reaction was stirred at thistemperature for 20 minutes. MeI (0.867 mL, 13.9 mmol) was added, and thereaction was warmed to room temperature. After 2 hours at roomtemperature, the mixture was poured onto saturated ammonium chloride (20mL) and extracted with ether, washed with brine and dried over sodiumsulfate. After removal of the solvent, the residue was purified bychromatography on silica gel (hexane:ethyl acetate 5:1) to give 1-benzyl3-ethyl 3-methylpiperidine-1,3-dicarboxylate (3.1 g, 98% yield) as anoil.

Step C: To 1-benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (3.0 g,10.0 mmol) in ethanol (15 mL) was added LiOH (15.0 mL, 30.1 mmol), andthe reaction mixture was stirred at 86° C. for 1 hour. The ethanol wasremoved, and ether (30 mL) was added. The aqueous layer was separatedand acidified with saturated potassium hydrogen sulfate to a pH of about3 to about 4, extracted with ethyl acetate (50 mL), and washed withbrine and dried over sodium sulfate. After removal of the solvent,1-(benzyloxycarbonyl)-3-methylpiperidine-3-carboxylic acid (2.6 g, 92%yield) was isolated as an oil.

Step D: DPPA (2.4 mL, 11.1 mmol) was added to1-(benzyloxycarbonyl)-3-methylpiperidine-3-carboxylic acid (2.5 g, 9.2mmol) and TEA (1.5 mL, 11.1 mmol) in t-BuOH (17.7 mL, 184.6 mmol). Themixture was heated at reflux for 6 hours and then was transferred to asealed tube and heated at 126° C. for 3 days. The solvent was removed,and then ether (50 mL) and saturated sodium bicarbonate (30 mL) wereadded. The organic layer was separated, washed with brine, dried oversodium sulfate. After removal of the solvent, the residue was purifiedby chromatography on silica gel (hexane:ethyl acetate 5:1) to givebenzyl 3-(tert-butoxycarbonylamino)-3-methylpiperidine-1-carboxylate(1.4 g, 43% yield) as a solid.

Step E: Benzyl3-(tert-butoxycarbonylamino)-3-methylpiperidine-1-carboxylate (1.4 g,4.0 mmol) and 10% Pd/C (0.21 g, 0.2 mmol) in MeOH (20 mL) were stirredunder H₂ atmosphere (1 atm) for 1 hour. The catalyst was removed byfiltration and washed with methanol. The filtrate was concentrated togive tert-butyl 3-methylpiperidin-3-ylcarbamate (0.62 g, 72% yield) as asolid.

Example D

tert-Butyl 3-methylpyrrolidin-3-ylcarbamate

Step A: To methyl pyrrolidine-3-carboxylate hydrochloride (4.00 g, 24.15mmol) and K₂CO₃ (6.68 g, 48.3 mmol) in 1:1 THF-water (100 mL) was addedbenzyl carbonochloridate (3.57 mL, 25.36 mmol) at 0° C. The reactionmixture was stirred at room temperature for 2 hours. Ether (50 mL) wasadded. The organic layer was separated, washed with brine and dried oversodium sulfate. After removal of the solvent, the residue was purifiedby chromatography (hexane:ethyl acetate 3:1) to give 1-benzyl 3-methylpyrrolidine-1,3-dicarboxylate (3.45 g, 54% yield) as an oil.

Step B: To 1-benzyl 3-methyl pyrrolidine-1,3-dicarboxylate (3.45 g, 13.1mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (16.4mL, 16.4 mmol) in THF at −78° C., and the reaction was stirred at thistemperature for 20 minutes. MeI (1.10 mL, 17.7 mmol) was added, and thereaction was warmed to room temperature. After 2 hours at roomtemperature, the mixture was poured onto saturated ammonium chloride (20mL) and extracted with ether, washed with brine and dried over sodiumsulfate. After removal of the solvent, the residue was purified bychromatography (hexane:ethyl acetate 4:1) to give 1-benzyl 3-methyl3-methylpyrrolidine-1,3-dicarboxylate (2.72 g, 75% yield) as an oil.

Step C: A 3M LiOH solution (14.7 mL, 29.4 mmol) was added to 1-benzyl3-methyl 3-methylpyrrolidine-1,3-dicarboxylate (2.72 g, 9.81 mmol) inethanol (15 mL), and the reaction mixture was stirred at 78° C. (bath)for 1 hour. The ethanol was removed, and ether (30 mL) was added. Theaqueous layer was separated and acidified with saturated potassiumhydrogen sulfate to a pH of about 3 to about 4, extracted with ethylacetate (50 mL), washed with brine and dried over sodium sulfate. Afterremoval of the solvent,1-(benzyloxycarbonyl)-3-methylpyrrolidine-3-carboxylic acid (2.56 g, 99%yield) was isolated as an oil.

Step D: DPPA (2.52 mL, 11.67 mmol) was added to1-(benzyloxycarbonyl)-3-methylpyrrolidine-3-carboxylic acid (2.56 g,9.72 mmol) and TEA (1.63 mL, 11.7 mmol) in t-BuOH (27.9 mL, 291.7 mmol).The mixture was heated at reflux for 1 hour and then was transferred toa sealed tube and heated at 100° C. (bath) for 24 hours. The solvent wasremoved, and ether (50 mL) and saturated sodium bicarbonate (30 mL) wereadded. The organic layer was separated, washed with brine and dried oversodium sulfate. After removal of the solvent, the residue was purifiedby chromatography (hexane:ethyl acetate 5:1) to give benzyl3-(tert-butoxycarbonylamino)-3-methylpyrrolidine-1-carboxylate (2.0 g,61% yield) as an oil.

Step E: Benzyl3-(tert-butoxycarbonylamino)-3-methylpyrrolidine-1-carboxylate (2.00 g,5.98 mmol) and 10% Pd/C (0.32 g, 0.30 mmol) in MeOH (20 mL) were stirredunder 1 atmosphere of H₂ for 1 hour. The catalyst was removed byfiltration and washed with methanol. The filtrate was concentrated togive tert-butyl 3-methylpyrrolidin-3-ylcarbamate (1.15 g, 96%) as asolid.

Example E

(R)-tert-Butyl methyl(piperidin-3-yl)carbamate

Step A: A solution of (R)-tert-butyl piperidin-3-ylcarbamate (10.00 g,49.93 mmol) and triethylamine (20.88 mL, 149.8 mmol) in CH₂Cl₂ (100 mL)at 0° C. (ice bath) was treated dropwise with benzyl carbonochloridate(10.54 mL, 74.90 mmol) and stirred at 0° C. After 2 hours, the mixturewas diluted with CH₂Cl₂ (50 mL) and successively washed with ice cold10% HCl (2×30 mL), water (1×30 mL), saturated NaHCO₃ (1×30 mL), andbrine (1×30 mL). The organic phase was dried (MgSO₄), filtered, andconcentrated in vacuo. The residue obtained was purified by flashchromatography on silica gel (Biotage Flash 60) eluting with 20%EtOAc/hexane (3 L). The fractions containing the product were pooled,concentrated in vacuo and dried under high vacuum for 18 hours toprovide (R)-benzyl 3-(tert-butoxycarbonylamino)piperidine-1-carboxylateas a solid. LCMS (APCI+) m/z 335 (M+H)+.

Step B: A solution of (R)-benzyl3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (5.00 g, 14.95mmol) in dry DMF (50 mL) was added dropwise to a suspension of sodiumhydride 60% in mineral oil (0.7176 g, 17.94 mmol) in dry DMF (10 mL).The mixture was stirred at 0° C. for 1 hour and allowed to stir at roomtemperature for 2 hours. Then the mixture was cooled to 0° C. andtreated dropwise with iodomethane (1.024 mL, 16.45 mmol). The reactionmixture was stirred at 0° C. for 1 hour and allowed to warm to roomtemperature over 18 hours. Water (40 mL) was added, and the mixture wasextracted into EtOAc (3×50 mL). The organic layers were combined, washedwith water (3×20 mL), dried (MgSO₄), filtered, and concentrated invacuo. The residue obtained was purified by flash chromatography onsilica gel (Biotage Flash 40M+) eluting with 20% EtOAc/hexane (1.25 L)to provide (R)-benzyl3-(tert-butoxycarbonyl(methyl)amino)piperidine-1-carboxylate (4.10 g,79% yield) as an oil. LCMS (APCI+) m/z 349 (M+H)+.

Step C: A solution of (R)-benzyl 3-(tert-butoxycarbonyl(methyl)amino)piperidine-1-carboxylate (4.00 g, 11.5 mmol) in methanol (10 mL) wasslowly added to a suspension of 5% Pd on activated carbon (2.44 g, 1.15mmol) in EtOH (20 mL). The reaction mixture was evacuated and backfilled with N₂ (3 cycles). The reaction vessel was then evacuated andback filled with H₂ (3 cycles) using a H₂ balloon. The mixture wasstirred under H₂ atmosphere for 1 hour and filtered through a pad ofcelite, washing with additional 10% MeOH/EtOAc (3×20 mL). The filtratecollected was concentrated in vacuo to provide (R)-tert-butylmethyl(piperidin-3-yl)carbamate (2.01 g, 82% yield) as an oil. LCMS(APCI+) nm/z 215 (M+H)+.

Example F

(R)-tert-Butyl ethyl (piperidin-3-yl)carbamate

Step A: A solution of (R)-benzyl3-(tert-butoxycarbonylamino)piperidine-1-carboxylate (5.00 g, 14.95mmol, Example E) in dry DMF (50 mL) was added dropwise to a suspensionof sodium hydride 60% in mineral oil (0.7176 g, 17.94 mmol) in dry DMF(10 mL). The mixture was stirred at 0° C. for 1 hour and allowed to stirat room temperature for 2 hours. The mixture was then cooled to 0° C.and treated dropwise with iodoethane (1.315 mL, 16.45 mmol). Thereaction mixture was stirred at 0° C. for 2 hours and allowed to warm toroom temperature over 18 hours. Water (50 mL) was added, and the mixturewas extracted into EtOAc (3×70 mL). The organic layers were combined,washed with water (3×20 mL), dried (MgSO₄), filtered, and concentratedin vacuo. The resulting residue was purified by flash chromatography onsilica gel (Biotage Flash 40M+) eluting with 20% EtOAc/hexane to provide(R)-benzyl 3-(tert-butoxycarbonyl(ethyl)amino)piperidine-1-carboxylate(5.01 g, 92% yield) as an oil, LCMS (APCI+) m/z 363 (M+H)+.

Step B: A solution of (R)-benzyl3-(tert-butoxycarbonyl(ethyl)amino)piperidine-1-carboxylate (5.00 g,13.8 mmol) in a mixture of EtOH:MeOH (1:1, 50 mL) was added to asuspension of 10% palladium on activated carbon (1.47 g, 1.38 mmol) inEtOH (20 mL) under N₂ atmosphere. The mixture was degassed under N₂ (3cycles) and back filled with H₂ (3 cycles) using a H₂ balloon. Themixture was then stirred under H₂ atmosphere for 4 hours. The reactionmixture was then filtered through a pad of celite washing with 5%MeOH/EtOAc (3×30 mL). The filtrate collected was concentrated in vacuoto provide the crude (R)-tert-butyl ethyl(piperidin-3-yl)carbamate. LCMS(APCI+) m/z 229 (M+H)+.

Example G

Benzyl-cis-4-fluoropiperidin-3-ylcarbamate

Step A: A solution of m-CPBA (7.53 g, 32.7 mmol) in DCM (10 mL) wasadded to a solution of tert-butyl 5,6-dihydropyridine-1(2H)-carboxylate(5.00 g, 27.3 mmol) in DCM (20 mL) at 0° C. The reaction was stirred at0° C. for 15 minutes and then at room temperature for 3 hours. Saturatedsodium sulfite solution (20 mL) and saturated sodium bicarbonatesolution (30 mL) was added. The organic layer was separated, washed withbrine, dried (sodium sulfate) and concentrated in vacuo to givetert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (5.36 g, 99%)as oil.

Step B: A mixture of tert-butyl7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (5.46 g, 27.4 mmol) andtriethylamine trihydrofluoride (4.42 g, 27.4 mmol) in DCE (4 mL) wasstirred at 80° C. (bath) for 18 hours. After cooling to roomtemperature, saturated sodium bicarbonate (20 mL) and DCM (30 mL) wereadded. The organic phase was separated, washed with brine, dried (sodiumsulfate) and concentrated in vacuo. The residue obtained was purified byflash chromatography on silica gel (hexane:ethyl acetate 1:1) to givetrans-tert-butyl 4-fluoro-3-hydroxypiperidine-1-carboxylate (3.5 g, 58%)as a solid.

Step C: A mixture of trans-tert-butyl4-fluoro-3-hydroxypiperidine-1-carboxylate (3.10 g, 14.1 mmol) and4-methylbenzene-1-sulfonyl chloride (5.39 g, 28.3 mmol) in pyridine (20mL) was stirred at room temperature for 18 hours. The pyridine wasremoved in vacuo, and the residue was dissolved in ethyl acetate (30mL), washed with brine, dried (sodium sulfate) and concentrated invacuo. The residue obtained was purified by flash chromatography onsilica gel (hexane:ethyl acetate 2:1) to give trans-tert-butyl4-fluoro-3-(tosyloxy)piperidine-1-carboxylate (3.95 g, 75%) as a solid.

Step D: A mixture of trans-tert-butyl4-fluoro-3-(tosyloxy)piperidine-1-carboxylate (3.95 g, 10.6 mmol) andNaN₃ (1.72 g, 26.4 mmol) in DMF (30 mL) was stirred at 128° C. (bath)for 18 hours. After cooling to room temperature, ether (100 mL) wasadded. The mixture was washed with brine (2×50 mL), dried (sodiumsulfate) and concentrated in vacuo. The residue obtained was purified byflash chromatography on silica gel (hexane:ethyl acetate 4:1) to givecis-tert-butyl 3-azido-4-fluoropiperidine-1-carboxylate (1.40 g, 54%).

Step E: A mixture of cis-tert-butyl3-azido-4-fluoropiperidine-1-carboxylate (1.40 g, 5.73 mmol) and 10%Pd/C (0.61 g, 0.57 mmol) in MeOH (20 mL) was charged 1 atmosphere H₂ andstirred at room temperature for 1 hour. The catalyst was removed byfiltration and washed with methanol. The filtrate was concentrated invacuo. The residue obtained was dissolved in pyridine (10 mL) and benzylcarbonochloridate (1.61 mL, 11.46 mmol) was added. The reaction wasstirred at room temperature for 2 hours. The pyridine was removed invacuo, and the residue was dissolved in ethyl acetate (30 mL), washedwith brine, dried (sodium sulfate) and concentrated in vacuo. Theresidue obtained was purified by flash chromatography on silica gel(hexane:ethyl acetate 3:1) to give cis-tert-butyl3-(benzyloxycarbonylamino)-4-fluoropiperidine-1-carboxylate (0.44 g,22%) as a solid.

Step F: 4N HCl in dioxane (3.29 mL, 13.2 mmol) was added to a solutionof cis-tert-butyl3-(benzyloxycarbonylamino)-4-fluoropiperidine-1-carboxylate (0.58 g,1.65 mmol) in DCM (3 mL) at room temperature. The reaction mixture wasstirred at room temperature for 2 hours. The solvent was removed invacuo. The resulting solid was dissolved in water (5 mL) and extractedwith ether (10 mL). The resulting aqueous layer was basified with 30%potassium carbonate to a pH of about 10 and extracted with DCM (2×30mL). The combined organic layer was dried (sodium sulfate) andconcentrated in vacuo to give benzyl-cis-4-fluoropiperidin-3-ylcarbamate(0.39 g, 94%) as a solid.

Example H

tert-Butyl-trans-4-methoxypiperidin-3-ylcarbamate

Step A: 3-Chlorobenzoperoxoic acid (51.1 g, 228 mmol) was added portionwise to a solution of 5,6-dihydropyridine-1(2H)-carboxylate (33.0 g, 152mmol) in DCM (200 mL) at 0° C. After 10 minutes at 0° C., the reactionwas warmed to room temperature and stirred at room temperature for 4hours. The reaction mixture was diluted with ether (800 mL), washed with1N NaOH solution (2×200 mL), saturated N₂SO₃ solution (2×100 mL), brine(100 mL), dried (sodium sulfate) and concentrated in vacuo to givebenzyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (35.0 g, 99%) asan oil.

Step B: A mixture of benzyl7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (19.0 g, 81.5 mmol), NaN₃(10.6 g, 163 mmol) and NH₄Cl (4.36 g, 81.5 mmol) in MeOH (200 mL) andwater (40 mL) was stirred at 65° C. (bath) for 20 hours. The reactionmixture was cooled to room temperature, and the methanol was removed invacuo. The resulting mixture was extracted with ether (2×300 mL). Thecombined ether layers were washed with brine, dried (sodium sulfate) andconcentrated in vacuo to give a mixture of trans-benzyl4-azido-3-hydroxypiperidine-1-carboxylate and trans-benzyl3-azido-4-hydroxypiperidine-1-carboxylate (22.0 g, 98%).

Step C: 4-Methylbenzene-1-sulfonyl chloride (31.9 g, 167 mmol) was addeddropwise to a mixture of trans-benzyl4-azido-3-hydroxypiperidine-1-carboxylate, trans-benzyl3-azido-4-hydroxypiperidine-1-carboxylate (22.0 g, 79.6 mmol) andpyridine (17 mL) in DCM (60 mL) at 0° C. After 5 minutes at 0° C., thereaction mixture was allowed warm to room temperature and stirred atroom temperature for 3 days. The solvent was removed in vacuo, and theresidue obtained was dissolved in ethyl acetate (300 mL). The mixturewas washed with brine, dried (sodium sulfate) and concentrated in vacuo.The residue obtained was purified by flash chromatography on silica gel(hexane:ethyl acetate 3:1) to give a mixture of trans-benzyl4-azido-3-(tosyloxy)piperidine-1-carboxylate and trans-benzyl3-azido-4-(tosyloxy)piperidine-1-carboxylate (37 g, 100%).

Step D: NaBH₄ (3.41 g, 90.3 mmol) was added portion wise to a solutionof CuSO₄-5H₂O (10.73 g, 42.98 mmol) in methanol (200 mL) at 0° C. After5 minutes, a solution of trans-benzyl4-azido-3-(tosyloxy)piperidine-1-carboxylate and trans-benzyl3-azido-4-(tosyloxy)piperidine-1-carboxylate (37 g, 85.95 mmol; mixedproduct from last step) in methanol (100 mL) was added at 0° C. Afteraddition, additional NaBH₄ (10.2 g, 270.6 mmol) was added in fourportions over the course of 1 hour. After one hour at 0° C., thereaction mixture was filtered through a pad of celite and concentratedin vacuo. The residue obtained was dissolved in DCM (800 mL), washedwith water (200 mL), saturated NH₄Cl solution (200 mL), brine (200 mL),dried (sodium sulfate) and concentrated in vacuo. The residue obtainedwas dissolved in DCM (200 mL) and TEA (24.0 mL, 171.9 mmol) and diethylphosphorochloridate (12.4 mL, 85.95 mmol) was added at 0° C. Thereaction mixture was warmed to room temperature and stirred at roomtemperature for 30 minutes. Water (50 mL) was added. The organic layerwas separated, washed with brine, dried (sodium sulfate) andconcentrated in vacuo. The residue obtained was purified by flashchromatography on silica gel (ethyl acetate) to give benzyl7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate(17.5 g, 55%) as an oil.

Step E: BF₃ etherate (1.35 mL, 10.6 mmol) was added to a solution ofbenzyl7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate(1.96 g, 5.32 mmol) in methanol (10 mL) at 0° C. and stirred at 0° C.for 2 hours. The solvent was removed in vacuo, ethyl acetate (30 mL) andsaturated sodium bicarbonate (20 mL) were added. The organic layer wasseparated, dried (sodium sulfate) and concentrated in vacuo to givetrans-benzyl3-(diethoxyphosphorylamino)-4-methoxypiperidine-1-carboxylate (2.00 g,94%) as an oil.

Step F: A mixture of trans-benzyl3-(diethoxyphosphorylamino)-4-methoxypiperidine-1-carboxylate (2.00 g,4.99 mmol) and 10% Pd/C (0.27 g, 0.25 mmol) in methanol (30 mL) wascharged with 1 atmosphere hydrogen and stirred at room temperature for 1hour. The catalyst was removed by filtration and washed with methanol(20 mL). The filtrate was concentrated in vacuo to give diethyltrans-4-methoxypiperidin-3-ylphosphoramidate (1.30 g, 98%) as an oil.

Step G: A mixture of diethyltrans-4-methoxypiperidin-3-ylphosphoramidate (1.30 g, 4.88 mmol),benzaldehyde (0.74 mL, 7.32 mmol) and acetic acid (0.56 mL, 9.76 mmol)in methanol (20 mL) was stirred at 0° C. for 30 minutes. NaCNBH₃ (0.46g, 7.32 mmol) was added at 0° C. The resulting solution was warmed toroom temperature and stirred at room temperature for 1 hour. The solventwas removed in vacuo and saturated sodium bicarbonate (20 mL) and ethylacetate (30 mL) were added. The organic layer was separated, washed withbrine, dried (sodium sulfate) and concentrated in vacuo to give diethyltrans-1-benzyl-4-methoxypiperidin-3-ylphosphoramidate (1.70 g, 98%),which was used directly in the next step without purification.

Step H: 6N HCl (5.56 mL, 33.4 mmol) was added to a solution of diethyltrans-1-benzyl-4-methoxypiperidin-3-ylphosphoramidate (1.7 g, 4.77 mmol)in dioxane (5 mL) at room temperature and stirred at 66° C. (bath) for 2hours. The solvent was removed in vacuo, and the residue obtained wasdissolved in THF (5 mL) and a 6N NaOH solution (7 mL). Boc₂O (2.08 g,9.54 mmol) was added, and the reaction mixture was stirred at roomtemperature for 1 hour. Ethyl acetate (20 mL) was added, and the organiclayer was separated, dried (sodium sulfate) and concentrated in vacuo.The residue obtained was purified by flash chromatography on silica gel(hexane:ethyl acetate 3:1) to give tert-butyltrans-1-benzyl-4-methoxypiperidin-3-ylcarbamate (1.37 g, 90%) as an oil.

Step I: A mixture of tert-butyltrans-1-benzyl-4-methoxypiperidin-3-ylcarbamate (1.37 g, 4.28 mmol) and10% Pd/C (0.46 g, 0.43 mmol) in MeOH (20 mL) was charged with 1atmosphere hydrogen and stirred at room temperature for 18 hours. Thecatalyst was removed by filtration and washed with methanol (20 mL). Thefiltrate was concentrated in vacuo to give tert-butyltrans-4-methoxypiperidin-3-ylcarbamate (0.99 g, 100%) as a solid.

Example I

Benzyl-trans-4-methylpiperidin-3-ylcarbamate

Step A: To a suspension of Cu(I)I (0.10 g, 0.54 mmol) in THF (20 mL) wasslowly added 1.40M methylmagnesium bromide (15.5 mL, 21.7 mmol) in 3:1toluene:THF at −30° C. After stirring at that temperature for 15minutes, a solution of benzyl7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate(2.00 g, 5.43 mmol, Example H, Step D) in THF (10 mL) was added at −30°C. The mixture was then slowly warmed to 0° C. in 2 hours and stirred at0° C. for 2 hours. Water (20 mL) was added and extracted with ethylacetate (2×30 mL), washed with brine, dried (sodium sulfate) andconcentrated in vacuo. The residue obtained was purified by flashchromatography on silica gel (ethyl acetate) to give trans-benzyl3-(diethoxyphosphorylamino)-4-methylpiperidine-1-carboxylate (1.00 g,48%) as an oil.

Step B: A mixture of trans-benzyl3-(diethoxyphosphorylamino)-4-methylpiperidine-1-carboxylate (0.95 g,2.5 mmol) and 10% Pd/C (0.13 g, 0.12 mmol) in methanol (30 mL) wascharged with 1 atmosphere hydrogen and stirred at room temperature for 1hour. The catalyst was removed by filtration and washed with methanol(20 mL). The filtrate was concentrated in vacuo to give diethyltrans-4-methylpiperidin-3-ylphosphoramidate (0.63 g, 100%) as an oil.

Step C: A mixture of diethyl trans-4-methylpiperidin-3-ylphosphoramidate(0.63 g, 2.52 mmol), benzaldehyde (0.38 mL, 3.78 mmol) and acetic acid(0.29 mL, 5.03 mmol) in methanol (20 mL) was stirred at 0° C. for 30minutes. NaCNBH₃ (0.24 g, 3.78 mmol) was added at 0° C. The resultingsolution was warmed to room temperature and stirred at room temperaturefor 1 hour. The solvent was removed in vacuo, and saturated sodiumbicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organiclayer was separated, washed with brine, dried (sodium sulfate) andconcentrated in vacuo to give diethyltrans-1-benzyl-4-methylpiperidin-3-ylphosphoramidate (0.85 g, 99%),which was used directly in the next step without purification.

Step D: 6N HCl (4.1 mL, 25 mmol) was added to a solution of diethyltrans-1-benzyl-4-methylpiperidin-3-ylphosphoramidate (0.85 g, 2.5 mmol)in dioxane (5 mL) at room temperature and stirred at 66° C. (bath) for 2hours. The solvent was removed in vacuo, and the residue obtained wasdissolved in THF (5 mL) and 6N NaOH (7 mL). Boc₂O (1.09 g, 5.0 mmol) wasadded and stirred at room temperature for 1 hour. Ethyl acetate (20 mL)was added, and the organic layer was separated, dried (sodium sulfate)and concentrated in vacuo. The residue obtained was purified by flashchromatography on silica gel (hexane:ethyl acetate 4:1) to givetert-butyl trans-1-benzyl-4-methylpiperidin-3-ylcarbamate (0.64 g, 84%)as a solid.

Step E: A mixture of tert-butyltrans-1-benzyl-4-methylpiperidin-3-ylcarbamate (0.64 g, 2.1 mmol) and10% Pd/C (0.22 g, 0.21 mmol) in methanol (10 mL) was charged with 1atmosphere hydrogen and stirred at room temperature for 18 hours. Thecatalyst was removed by filtration and washed with methanol (20 mL). Thefiltrate was concentrated in vacuo to give tert-butyltrans-4-methylpiperidin-3-ylcarbamate (0.43 g, 95%) as a solid.

Example J

tert-Butyl-trans-4-fluoropiperidin-3-ylcarbamate

Step A: BF₃ etherate (3.10 mL, 24.4 mmol) was added to a solution ofbenzyl7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate(3.00 g, 8.14 mmol; Example H, step D) in DCM (10 mL) at 0° C. Theresulting solution was warmed to room temperature and stirred at roomtemperature for 3 days. The solvent was removed in vacuo, ethyl acetate(30 mL) and saturated sodium bicarbonate (20 mL) were added. The organiclayer was separated, dried (sodium sulfate) and concentrated in vacuo.The residue obtained was purified by flash chromatography on silica gel(ethyl acetate) to give trans-benzyl3-(diethoxyphosphorylamino)-4-fluoropiperidine-1-carboxylate (0.53 g,17%) as oil.

Step B: A mixture of trans-benzyl3-(diethoxyphosphorylamino)-4-fluoropiperidine-1-carboxylate (0.54 g,1.4 mmol) and 10% Pd/C (0.074 g, 0.070 mmol) in methanol (30 mL) wascharged with 1 atmosphere hydrogen and stirred at room temperature for 6hours. The catalyst was removed by filtration and washed with methanol(20 mL). The filtrate was concentrated in vacuo to give diethyltrans-4-fluoropiperidin-3-ylphosphoramidate (0.35 g, 99%) as oil.

Step C: A mixture of diethyl trans-4-fluoropiperidin-3-ylphosphoramidate(0.35 g, 1.38 mmol), benzaldehyde (0.21 mL, 2.07 mmol) and acetic acid(0.16 mL, 2.75 mmol) in methanol (20 mL) was stirred at 0° C. for 30minutes. NaCNBH₃ (0.13 g, 2.07 mmol) was added at 0° C. The resultingsolution was warmed to room temperature and stirred at room temperaturefor 1 hour. The solvent was removed in vacuo, and saturated sodiumbicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organiclayer was separated, washed with brine, dried (sodium sulfate) andconcentrated in vacuo to give diethyltrans-1-benzyl-4-fluoropiperidin-3-ylphosphoramidate (0.47 g, 99%),which was used directly in the next step without purification.

Step D: 6N HCl (4.55 mL, 27.30 mmol) was added to a solution of diethyltrans-1-benzyl-4-fluoropiperidin-3-ylphosphoramidate (0.47 g, 1.37 mmol)in dioxane (5 mL) and stirred at 66° C. (bath) for 2 hours. The solventwas removed in vacuo, and the residue obtained was dissolved in THF (5mL) and 6N NaOH (7 mL). Boc₂O (0.60 g, 2.73 mmol) was added and stirredat room temperature for 1 hour. Ethyl acetate (20 mL) was added, and theorganic layer was separated, dried (sodium sulfate) and concentrated invacuo. The residue obtained was purified by flash chromatography onsilica gel (hexane:ethyl acetate=4:1) to give tert-butyltrans-1-benzyl-4-fluoropiperidin-3-ylcarbamate (0.28 g, 67%) as a solid.

Step E: A mixture of tert-butyltrans-1-benzyl-4-fluoropiperidin-3-ylcarbamate (0.28 g, 0.91 mmol) and10% Pd/C (0.097 g, 0.091 mmol) in MeOH (10 mL) was charged 1 atmosphereof hydrogen and stirred at room temperature for 4 hours. The catalystwas removed by filtration and washed with methanol (20 mL). The filtratewas concentrated in vacuo to give tert-butyltrans-4-fluoropiperidin-3-ylcarbamate (0.19 g, 96%) as oil.

Example K

tert-Butyl-trans-4-cyclopropylpiperidin-3-ylcarbamate

Step A: To a suspension of Cu(I)I (0.15 g, 0.77 mmol) in THF (20 mL) wasslowly added 0.50M cyclopropylmagnesium bromide (61.2 mL, 30.6 mmol) inTHF at −30° C. After stirring at that temperature for 15 minutes, asolution of benzyl7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate(2.82 g, 7.66 mmol; Example H, Step D) in THF (10 mL) was added at −30°C., and then the mixture was slowly warmed to room temperature andstirred at room temperature for 2 hours. Water (50 mL) was added andextracted with ethyl acetate (2×40 mL), washed with brine, dried (sodiumsulfate) and concentrated in vacuo. The residue obtained was purified byflash chromatography on silica gel (ethyl acetate) to give trans-benzyl4-cyclopropyl-3-(diethoxyphosphorylamino)piperidine-1-carboxylate (1.84g, 59%).

Step B: A mixture of trans-benzyl4-cyclopropyl-3-(diethoxyphosphorylamino) piperidine-1-carboxylate (1.84g, 4.48 mmol) and 10% Pd/C (0.48 g, 0.45 mmol) in methanol (30 mL) wascharged with 1 atmosphere hydrogen and stirred at room temperature for 1hour. The catalyst was removed by filtration and washed with methanol(20 mL). The filtrate was concentrated in vacuo to give diethyltrans-4-cyclopropylpiperidin-3-ylphosphoramidate (1.24 g, 100%) as anoil.

Step C: A mixture of diethyltrans-4-cyclopropylpiperidin-3-ylphosphoramidate (1.24 g, 4.49 mmol),benzaldehyde (0.68 mL, 6.73 mmol) and acetic acid (0.51 mL, 8.98 mmol)in methanol (20 mL) was stirred at 0° C. for 30 minutes. NaCNBH₃ (0.42g, 6.73 mmol) was added at 0° C. The resulting solution was warmed toroom temperature and stirred at room temperature for 1 hour. The solventwas removed in vacuo, and saturated sodium bicarbonate (20 mL) and ethylacetate (30 mL) were added. The organic layer was separated, washed withbrine, dried (sodium sulfate) and concentrated in vacuo to give diethyltrans-1-benzyl-4-cyclopropylpiperidin-3-ylphosphoramidate (1.64 g,100%), which was used directly in the next step without purification.

Step D: 6N HCl (7.46 mL, 44.76 mmol) was added to a solution of diethyltrans-1-benzyl-4-cyclopropylpiperidin-3-ylphosphoramidate (1.64 g, 4.48mmol) in dioxane (5 mL) and stirred at 66° C. (bath) for 2 hours. Thesolvent was removed in vacuo, and the residue obtained was dissolved inTHF (5 mL) and 6N NaOH (7 mL). Boc₂O (1.95 g, 8.95 mmol) was added andstirred at room temperature for 1 hour. Ethyl acetate (20 mL) was added,and the organic layer was separated, dried (sodium sulfate) andconcentrated in vacuo. The residue obtained was purified by flashchromatography on silica gel (hexane:ethyl acetate=3:1) to givetert-butyl trans-1-benzyl-4-cyclopropylpiperidin-3-ylcarbamate (1.20 g,81%) as a solid.

Step E: A mixture of tert-butyltrans-1-benzyl-4-cyclopropylpiperidin-3-ylcarbamate (1.20 g, 3.63 mmol)and 10% Pd/C (0.39 g, 0.36 mmol) in methanol (20 mL) was charged with 1atmosphere hydrogen and stirred at room temperature for 18 hours. Thecatalyst was removed by filtration and washed with methanol (20 mL). Thefiltrate was concentrated in vacuo to givetert-butyl-trans-4-cyclopropylpiperidin-3-ylcarbamate (0.87 g, 100%) asa solid.

Example L

5-Chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine

4-Fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 10.258mmol) was placed in THF (15 mL) at −78° C. s-BuLi (16.12 mL, 22.57 mmol)was then added dropwise and stirred for 30 minutes. Hexachloroethane(6.07 g, 25.6 mmol) in THF (10 mL) was then added rapidly, and thereaction was stirred for an additional 30 minutes. The reaction wasquenched with saturated aqueous NH₄Cl and extracted into hexanes. Thecombined organic fractions were dried, filtered and concentrated to givethe crude product that was purified by column chromatography (hexanes)to give5-chloro-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.1g, 62% yield).

5-Chloro-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0g, 9.18 mmol) was placed in THF (15 mL) at 0° C. TBAF (10.094 mL, 10.094mmol) was added dropwise and stirred for 30 minutes. The reaction wasthen quenched with saturated aqueous NaHCO₃ and extracted into DCM. Thecombined organic fractions were dried, filtered, and concentrated togive the crude product that was purified by column chromatography (500:6DCM:MeOH) to give 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridine (1.4 g,89% yield).

5-Chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridine (1.2 g, 7.0 mmol) was addedslowly to fuming nitric acid (10 mL) at 0° C. Upon completion of theaddition, the reaction was stirred for 10 minutes, and then quenchedwith ice. Water was added until a precipitate formed, which wasfiltered, washed with water and dried to give the product5-chloro-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (1.3 g, 86% yield).

5-Chloro-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (1.20 g, 5.57 mmol)was placed in 6M HCl (30 mL). SnCl₂ (5.28 g, 27.8 mmol) was then added,and the reaction was stirred for 30 minutes at room temperature. Thereaction was then poured into a mixture of 1M NaOH and ice. Theresulting suspension was then raised to a pH of 8 and then extractedwith 3:1 DCM:i-PrOH. The combined organic fractions were dried,filtered, and concentrated to give the crude product, which wastriturated with 10:1 hexanes:DCM to give the product5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.8 g, 77% yield).

Example 1

N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: A solution of 3-chlorobenzoperoxoic acid (121 g, 698 mmol) inethyl acetate (“EtOAc”; 500 mL) was added dropwise over 1 hour to1H-pyrrolo[2,3-b]pyridine (75.0 g, 635 mmol) in EtOAc (1.5 L) at 0° C.The reaction was stirred for 4 hours at room temperature. The resultingsuspension was filtered and dried under high vacuum to provide1H-pyrrolo[2,3-b]pyridine N-oxide, 3-chlorobenzoic acid salt (135 g, 73%yield) as a solid. This material was dissolved in water (500 mL), and30% aqueous potassium carbonate was added to bring the pH to about 9 to10. The reaction was stirred for 1 hour, and then it was cooled to about0-5° C. The precipitate that formed was filtered and washed with waterand then dried under high vacuum to provide 1H-pyrrolo[2,3-b]pyridineN-oxide (42 g, 67% yield) as a solid.

Step B: Tetramethylammonium bromide (72 g, 470 mmol) was added to1H-pyrrolo[2,3-b]pyridine N-oxide (42 g, 313 mmol) in DMF (500 mL) at 0°C., which was followed by addition of methanesulfonic anhydride (109 g,626 mmol). The suspension was warmed to room temperature and stirred atroom temperature for 18 hours. Water (200 mL) was added, and thesolution was neutralized with addition of 50% NaOH. The resultingsolution was then further diluted with water (500 mL) and cooled to 0°C. The precipitate formed was collected, rinsed with water and dilutedin CH₂Cl₂/MeOH (500 mL, 3:1 v/v). This solution was dried (MgSO₄),filtered and concentrated in vacuo to yield4-bromo-1H-pyrrolo[2,3-b]pyridine (33 g, 53% yield) as a solid. ¹H NMR(400 MHz, (CD₃)₂SO) δ 12.05 (br s, 1H), 8.10 (d, 1H), 7.61 (dd, 1H),7.34 (d, 1H), 6.43 (dd, 1H); LCMS (APCI+) m/z 196.9, 198.9 (M+H)+,Retention time=2.59 minutes (Method 1).

Step C: Sodium hydride (8.37 g, 209 mmol; 60% oil dispersion) was slowlyadded to 4-bromo-1H-pyrrolo[2,3-b]pyridine (33.0 g, 167 mmol) in THF(500 mL) at 0° C. The reaction was stirred for 15 minutes.Chlorotriisopropylsilane (38.7 g, 201 mmol) was then added in oneportion. The suspension was warmed to room temperature and stirred for30 minutes. The suspension was then cooled to about 0-5° C. and quenchedwith saturated aqueous NH₄Cl (about 200 mL). The aqueous phase wasextracted with hexanes (3×300 mL), and the combined organic phases weredried (MgSO₄) and concentrated in vacuo. The residue was purified byflash chromatography on silica gel eluting with hexanes to yield4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (50 g, 84%yield) as an oil, which solidified upon standing. ¹H NMR (400 MHz,CDCl₃) δ 8.05 (d, 1H), 7.34 (d, 1H), 7.22 (d, Hz, 2H), 6.59 (d, 1H),1.88-1.80 (m, 3H), 1.11 (d, 18H).

Step D: 4-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (50 g,141.5 mmol) in THF (2 L) at −78° C. was treated dropwise withtert-butyllithium (166.5 mL, 283.0 mmol, 1.7M in pentane). The reactionwas then stirred for 15 minutes.N-Fluoro-N-(phenylsulfonyl)benzenesulfonamide (49.08 g, 155.6 mmol) inTHF (200 mL) was then added dropwise, and the mixture was stirred at−78° C. After 2 hours, the reaction was quenched at −78° C. withsaturated aqueous NH₄Cl (200 mL). The aqueous phase was extracted withhexanes. The combined hexane phases were dried (MgSO₄) and passedthrough a plug of silica gel eluting with hexanes. The combined hexanesfractions were concentrated in vacuo to provide4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (36.1 g, 87%yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ □8.18 (dd, 1H), 7.25 (d,1H), 6.76 (dd, 1H), 1.86-1.81 (m, 3H), 1.13 (d, 18H).

Step E: 4-Fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (28.0g, 95.7 mmol) in THF (600 mL) at −78° C. was treated dropwise withsec-butyllithium (150 mL, 211 mmol; 1.4M in cyclohexane). The reactionwas stirred at −78° C. for 30 minutes. Perbromomethane (79.4 g, 239mmol) in THF (100 mL) was then added dropwise. The reaction was stirredat −78° C. for 1 hour and then quenched with saturated aqueous NH₄Cl.The aqueous phase was extracted with hexanes. The combined organicphases were dried (MgSO₄) and concentrated in vacuo. The oil obtainedwas purified by flash chromatography on silica gel eluting with hexanesto provide5-bromo-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (30 g,84% yield) as an oil, which solidified upon standing. ¹H NMR (400 MHz,CDCl₃) δ 8.28 (d, 1H). 7.26 (s, 1H), 6.62 (d, 1H), 1.86-1.78 (m, 3H),1.11 (d, 18H).

Step F: TBAF.3H₂O (80.8 mL, 80.8 mmol; 1.0M solution in THF) was addedto 5-bromo-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine(30.0 g, 80.8 mmol) in THF (200 mL) at room temperature. The reactionwas stirred for 20 minutes, and then water (200 mL) and ether (500 mL)were added. The aqueous phase was extracted with ether. The combinedorganic phases were washed with brine, dried (MgSO₄) and concentrated invacuo. The solid was crystallized from EtOAc to provide5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (12.5 g, 72% yield). ¹H NMR(400 MHz, CDCl₃) δ 11.06 (br s, 1H), 8.39 (d, 1H), 7.35 (dd, 1H), 6.60(dd, 1H); LCMS (APCI+) m/z 214.9, 216.9 (M+H)+, Retention time=2.75minutes (Method 1).

Step G: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (10 g, 47 mmol) wasadded to fuming nitric acid (50 mL) at 0° C., and the reaction wasstirred at 0° C. for 30 minutes. Ice (300 mL) was added, and thereaction was allowed to warm to room temperature. The resultingsuspension was filtered and dried under high vacuum to provide5-bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (9.2 g, 76% yield) asa solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 13.63 (br s, 1H), 8.85 (s, 1H),8.56 (d, 1H).

Step H: Tin (II) chloride (10 g, 54 mmol) was slowly added to5-bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (9.0 g, 35 mmol) in6N HCl (200 mL) at a temperature of about 0° C. to about 5° C., and thereaction was stirred at room temperature for 2 hours. The reaction pHwas raised to 7 by addition of 6N NaOH. The aqueous layer was thenextracted with CHCl₃/i-PrOH (3:1). The combined organic phases weredried (MgSO₄) and concentrated in vacuo to yield5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (5.1 g, 64% yield) asa solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.18 (br s, 1H), 8.13 (d, 1H),6.66 (d, 1H), 4.21 (s, 2H); LCMS (APCI+) m/z 229.9, 231.9 (M+H)+,Retention time=2.11 minutes (Method 1).

Step I: A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(3.0 g, 13 mmol) in CH₂Cl₂ (200 mL) was treated with nicotinic acid (3.2g, 26 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (6.6 g, 26mmol) and triethylamine (6.6 g, 65 mmol). The reaction was stirred atroom temperature for 1 hour, and then 3M aqueous LiOH (4 mL) was added.The reaction was stirred for 1 hour, and then saturated aqueous Na₂CO₃was added (200 mL). The aqueous phase was extracted with CH₂Cl₂ (1×200mL), and the aqueous phase was filtered. The filtered cake was dried toyield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(3.5 g, 80% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 9.09 (d, 1H), 8.72 (dd,1H), 8.32 (d. 1H), 8.26 (d, 1H), 7.50 (dd, 1H); LCMS (APCI+) m/z 336.9(M+H)+, Retention time=2.19 minutes (Method 1).

Step J: A solution ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (120 mg,0.358 mmol) in n-BuOH (5 mL) was treated with tert-butylpiperidin-3-ylcarbamate (359 mg, 1.79 mmol) and stirred at 160° C. for20 hours in a sealed tube. The mixture was concentrated in vacuo, andthe residue was purified by C-18 reverse phase flash chromatography(Biotage SP4 unit, C-18 25M column, 20-80% CH₃CN/water gradient; 20 CV)to provide tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(60 mg, 32% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 10.10 (br s,1H), 9.27 (m, 1H), 9.19 (d, 1H), 8.79 (d, 1H), 8.33-8.29 (m, 2H), 8.18(br s, 1H), 7.51-7.47 (m, 1H), 4.54-4.78 (m, 1H), 3.84-3.69 (m, 1H),3.64-3.41 (m, 3H), 3.08-2.95 (m, 1H), 2.09-1.96 (m, 1H), 1.92-1.50 (m,2H), 1.42 (s, 9H); LCMS (APCI+) m/z 515.1, 517.1 (M+H)+, Retentiontime=2.83 minutes (Method 1).

Step K: A solution of tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(50 mg, 0.097 mmol) in TFA (5 mL) was stirred at room temperature for 30minutes and concentrated in vacuo. The residue was dissolved in minimalmethanol, and the solution was added to a 2N HCl ether solution. Theprecipitate formed was filtered and dried under high vacuum to yieldN-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (22 mg, 52% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.06 (s,1H), 10.47 (br s, 1H), 9.38 (d, 1H), 8.96 (dd, 1H), 8.75 (d, 1H), 8.28(s, 1H), 8.24 (br s, 2H), 7.92 (dd, 1H), 7.61 (s, 1H), 3.51-3.45 (m,1H), 3.38-3.26 (m, 1H), 3.23-3.06 (m, 3H), 1.94-1.84 (m, 1H), 1.67-1.59(m, 1H), 1.48-1.24 (m, 2H); LCMS (APCI+) m/z 415, 417.0 (M+H)+,Retention time=1.78 minutes (Method 1).

Example 1A

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: Solid (R)-tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(52 mg, 34% yield) was prepared as described in Example 1, Step J, usingN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg,0.298 mmol, Example 1, Step I) and substituting (R)-tert-butylpiperidin-3-ylcarbamate (179 mg, 0.895 mmol) for tert-butylpiperidin-3-ylcarbamate.

Step B: Solid(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (12 mg, 33% yield) was prepared as described in Example 1,Step K, substituting (R)-tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamatefor tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate.¹H NMR (400 MHz, (CD₃)₂SO) δ 12.06 (d, 1H), 10.47 (br s, 1H), 9.39 (d,1H), 8.96 (dd, 1H), 8.79 (d, 1H), 8.28 (s, 1H), 8.24 (br s, 3H), 7.92(dd, 1H), 7.61 (d, 1H), 3.52-3.44 (m, 1H), 3.37-3.28 (m, 1H), 3.22-3.08(m, 3H), 1.95-1.85 (m, 1H), 1.67-1.56 (m, 1H), 1.50-1.27 (m, 2H); LCMS(APCI+) m/z 415, 417.0 (M+H)+, Retention time=1.78 minutes (Method 1).

Example 1B

(S)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: (S)-tert-Butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(63 mg, 41%) was prepared as described in Example 1, Step J, usingN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg,0.298 mmol, Example 1, Step I) and substituting (S)-tert-butylpiperidin-3-ylcarbamate (179 mg, 0.895 mmol) for tert-butylpiperidin-3-ylcarbamate.

Step B:(S)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (8 mg, 20% yield) was prepared as described in Example 1,Step K, substituting (S)-tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamatefor tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate.¹H NMR (400 MHz, (CD₃)₂SO) δ 11.93 (d, 1H), 10.14 (br s, 1H), 9.21 (d,1H), 8.79 (dd, 1H), 8.56-8.41 (m, 1H), 8.22 (s, 1H), 7.99 (br s, 1H),7.64 (dd, 1H), 3.45-323 (m, 2H), 3.18-2.98 (m, 4H), 1.87-1.51 (m, 1H),1.48-1.13 (m, 2H); LCMS (APCI+) m/z 415, 417.0 (M+H)+, Retentiontime=1.78 minutes (Method 1).

Example 2

N-(5-Bromo-4-(3-(dimethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

N,N-Dimethylpiperidin-3-amine (115 mg, 0.895 mmol) was added toN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg,0.298 mmol) in n-BuOH. The reaction was stirred at 160° C. for 20 hoursin a sealed tube. After concentration, the residue was purified by C-18reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column,0-60% CH₃CN/water gradient; 20 CV) to yieldN-(5-bromo-4-(3-(dimethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(60 mg, 45.4% yield) as a solid. The solid was dissolved in a minimalamount of methanol, and then the solution was added to 2N HCl in ether.The resulting precipitate was filtered and dried under high vacuum toyieldN-(5-bromo-4-(3-(dimethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 10.91 (d, 1H),10.63 (br s, 1H), 9.47 (d, 1H), 8.99 (dd, 1H), 8.90 (d, 1H), 8.30 (s,1H), 7.98 (dd, 1H), 7.59 (s, 1H), 3.67-3.59 (m, 1H), 3.27-3.06 (m, 3H),2.76-2.67 (m, 1H), 2.68 (d, 3H), 2.65 (d, 3H), 2.14-2.04 (m, 1H),1.74-1.66 (m, 1H), 1.59-1.32 (m, 2H); LCMS (APCI+) m/z 443, 445 (M+H)+,Retention time=1.90 minutes (Method 1).

Example 3

N-(4-(3-(Aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

N-(4-(3-(Aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (6 mg, 83% yield) was prepared as described in Example 1,Steps J and K, usingN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (20 mg,0.060 mmol; Example 1, Step I) and substituting tert-butylpyrrolidin-3-ylmethylcarbamate (60 mg, 0.30 mmol) for tert-butylpiperidin-3-ylcarbamate. ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.91 (d, 1H),10.27 (s, 1H), 9.18 (d, 1H), 8.62 (dd, 1H), 8.43 (dt, 1H), 8.31 (s, 1H),7.98 (br s, 3H), 7.76-7.72 (m, 2H), 3.65-3.61 (m, 1H), 3.54-3.44 (m,2H), 3.27-3.21 (m, 1H), 2.86-2.76 (m, 1H), 2.68-2.52 (m, 2H), 2.12-2.01(m, 1H), 1.68-1.58 (m, 1H); LCMS (APCI+) m/z 415, 417 (M+H)+, Retentiontime=1.87 minutes (Method 1).

Example 3A

(S)—N-(4-(3-(Aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Solid(S)—N-(4-(3-(aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (160 mg, 86% yield) was prepared as described in Example1, Steps J and K, usingN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (400 mg,1.19 mmol; Example 1, Step I) and substituting (R)-tert-butylpyrrolidin-3-ylmethylcarbamate (717 mg, 3.58 mmol) for tert-butylpiperidin-3-ylcarbamate. 1H NMR (400 MHz, (CD₃)₂SO) δ 11.99 (d, 1H),10.42 (s, 1H), 9.25 (d, 1H), 8.94 (dd, 1H), 8.61 (dt, 1H), 8.31 (d, 1H),8.11 (br s, 3H), 7.89 (dd, 1H), 7.70 (d, 1H), 3.65-3.62 (m, 1H),3.58-3.46 (m, 2H), 3.20-3.26 (m, 1H), 2.85-2.76 (m, 2H), 2.63-2.53 (m,1H), 2.12-2.01 (m 1H), 1.69-1.60 (m, 1H); LCMS (APCI+) m/z 415, 417(M+H)+, Retention time=1.87 minutes (Method 1).

Example 3B

(R)—N-(4-(3-(Aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Solid(R)—N-(4-(3-(aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (64 mg, 13% yield) was prepared as described in Example 1,Steps J and K, usingN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (400 mg,1.19 mmol) and substituting (S)-tert-butylpyrrolidin-3-ylmethylcarbamate (717 mg, 3.58 mmol) for tert-butylpiperidin-3-ylcarbamate. ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.98 (d, 1H),10.41 (s, 1H), 9.24 (d, 1H), 8.93 (dd, 1H), 8.59 (dt, 1H), 8.31 (s, 1H),8.10 (br s, 1H), 7.87 (dd, 1H), 7.71 (d, 1H), 3.68-3.64 (m, 1H0,3.57-3.46 (m, 2H), 3.30-3.26 (m, 1H), 2.86-2.77 (m, 2H), 2.63-2.55 (m,1H), 2.11-2.03 (m, 1H), 1.69-1.60 (m, 1H); LCMS (APCI+) m/z 415, 417(M+H)+, Retention time=1.94 minutes (Method 1).

Example 4

N-(5-Bromo-4-(2,7-diazaspiro[4.4]nonan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

N-(5-Bromo-4-(2,7-diazaspiro[4.4]nonan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (8 mg, 33% yield) was prepared as described in Example 1,Steps J and K, substituting tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate (135 mg, 0.597 mmol) fortert-butyl piperidin-3-ylcarbamate. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.03(d, 1H), 10.36 (s, 1H), 9.58-9.39 (m, 2H), 9.31 (d, 1H), 8.91 (dd, 1H),8.63 (dt, 1H), 8.31 (s, 1H), 7.82 (dd, 1H), 7.64 (d, 1H), 3.59-3.52 (m,2H), 3.46 (d, 2H), 3.25-3.20 (m, 2H), 3.14-3.08 (m, 2H), 1.95-1.85 (m,2H), 1.81-1.68 (m, 2H); LCMS (APCI+) m/z 441, 443 (M+H)+, Retentiontime=1.87 minutes (Method 1).

Example 5

(R)—N-(4-(3-Aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: (R)-tert-Butyl pyrrolidin-3-ylcarbamate (333 mg, 1.79 mmol) wasadded to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(200 mg, 0.597 mmol) in n-BuOH (3 mL), and the reaction was stirred at160° C. for 24 hours. The reaction was concentrated to dryness, and thenthe residue was purified by chromatography (SP4, C-18 25M+ column,gradient of 10-90% CH₃CN/water, 30CV) to yield (R)-tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate(105 mg, 35.1% yield) as a solid.

Step B: (R)-tert-Butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate(90 mg, 0.18 mmol) was dissolved in TFA (5 mL) and stirred at roomtemperature for 30 minutes. The reaction was concentrated to dryness andthen dissolved in a minimal amount of methanol. The solution was addeddropwise to a stirred solution of 4N HCl in dioxane. The resulting solidwas filtered and dried under high vacuum to yield(R)—N-(4-(3-aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (20 mg, 28% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 12.01 (d, 1H), 10.38 (s, 1H), 9.29 (d, 1H), 8.93 (dd, 1H), 8.67 (d,1H), 8.38 (br s, 3H), 8.30 (s, 1H), 7.88 (dd, 1H), 7.68 (d, 1H),3.83-3.78 (m, 1H), 3.75-3.67 (m 1H), 3.65-3.59 (m, 1H), 3.58-3.54 (m,1H), 3.49-3.42 (m, 1H), 2.21-2.13 (m, 1H), 1.95-1.86 (m, 1H); LCMS(APCI+) m/z 401, 403 (M+H)+, Retention time=1.94 minutes (Method 1).

Example 6

(S)—N-(5-Bromo-4-(3-(isopropylamino)methyl)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

DIEA (0.023 mL, 0.133 mmol) was added to a solution of(S)—N-(4-(3-(aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (70 mg, 0.13 mmol; Example 3A) and propan-2-one (77.4 mg,1.33 mmol) in CH₂Cl₂:DMF (1:1, 3 mL), followed by the addition ofNaBH(OAc)₃ (57 mg, 0.26 mmol). The reaction was stirred for 30 minutes.The reaction mixture was then poured into a solution of Na₂CO₃ andextracted into CH₂Cl₂. The organic phases were combined, dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by reversephase HPLC (Gilson system). The isolated product was then dissolved inminimal CH₂Cl₂ (with MeOH to aid solubility) and added to 1M HCl inether (10 mL). The solid formed was collected to provide(S)—N-(5-bromo-4-(3-((isopropylamino)methyl)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (40 mg, 53% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.08 (d,1H), 10.58 (s, 1H), 9.32 (d, 1H), 8.98 (dd, 1H), 8.76 (dt, 1H), 8.32 (s,1H), 7.99 (dd, 1H), 7.67 (d, 1H), 3.77-3.73 (m, 1H), 3.60-3.52 (m, 2H),3.39-3.34 (m, 1H), 3.23-3.16 (m, 1H), 2.91-2.85 (m, 2H), 2.73-2.66 (m,1H), 2.14-2.07 (m, 1H), 1.74-1.64 (m, 1H), 1.22 (d, 6H); LCMS (APCI+)m/z 459.1, 460.1 (M+H)+.

Example 7

(R)—N-(4-(3-(Aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

Step A: N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (10mg, 7% yield) was prepared as described in Example 1, Step I, using5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (100 mg, 0.435 mmol)and substituting benzoic acid (112 mg, 0.913 mmol) for nicotinic acid.¹H NMR (400 MHz, (CD₃)₂SO) δ 12.16 (br s, 1H), 10.06 (s, 1H), 8.38 (d,1H), 7.98 (dd, 1H), 7.64-7.52 (m, 5H); LCMS (APCI+) m/z 333.9 (M+H)+,Retention time=3.11 minutes (Method 2).

Step B:(R)—N-(4-(3-(Aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamidehydrochloride (15 mg, 37% yield) was prepared as described in Example 1,Steps J and K, substitutingN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (75 mg, 0.22mmol) for N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamideand (S)-tert-butyl pyrrolidin-3-ylmethylcarbamate (130 mg, 0.67 mmol)for tert-butyl piperidin-3-ylcarbamate. ¹H NMR (400 MHz, (CD₃)₂SO) δ11.85 (s, 1H), 10.14 (s, 1H), 8.31 (s, 1H), 8.07 (br s, 3H), 7.93 (dd,2H), 7.78 (d, 1H), 7.64-7.61 (m, 3H), 3.65-3.62 (m, 1H), 3.55-3.47 (m,2H), 3.30-3.26 (m, 1H), 2.88-2.82 (m, 2H), 2.71-2.63 (m, 1H), 2.18-2.10(m, 1H), 1.76-1.67 (m, 1H); LCMS (APCI+) m/z 414.0 (M+H)+, Retentiontime=2.30 minutes (Method 2).

Example 8

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A:5-Chloro-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.1g, 62% yield) was prepared as described in Example 1, Step E, using4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0 g, 10.26mmol) and substituting hexachloroethane (6.07 g, 25.64 mmol) forperbromomethane.

Step B:5-Chloro-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3.0g, 9.2 mmol) in THF (15 mL) at 0° C. was treated dropwise with TBAF(10.1 mL, 10.1 mmol). After 30 minutes, the reaction was quenched withsaturated aqueous NaHCO₃ and extracted into CH₂Cl₂. The combined organicfractions were dried (MgSO₄), filtered, and concentrated in vacuo. Thecrude was purified by flash chromatography on silica gel using 1.2%MeOH:CH₂Cl₂ to provide 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridine (1.4g, 89% yield).

Step C: 5-Chloro-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (1.3 g, 86%yield) was prepared as described in Example 1, Step G, substituting5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridine (1.2 g, 7.0 mmol) for5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine.

Step D: 5-Chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.8 g, 77%yield) was prepared as described in Example 1, Step H, substituting5-chloro-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (1.20 g, 5.56 mmol)for 5-bromo-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine. LCMS (APCI+) m/z186.2 (M+H)+.

Step E: N-(5-Chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(0.42 g, 67% yield) was prepared as described in Example 1, Step I,substituting 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (400 mg,2.155 mmol) for 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine. LCMS(APCI+) m/z 291.0 (M+H)+, Retention time=2.45 min (Method 2).

Step F:(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (90 mg, 74% yield) was prepared as described in Example 1,Steps J and K, substitutingN-(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (200 mg,0.688 mmol) forN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide and(R)-tert-butyl piperidin-3-ylcarbamate (276 mg, 1.38 mmol) fortert-butyl piperidin-3-ylcarbamate. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.01(d, 1H), 10.39 (s, 1H), 9.35 (s, 1H), 8.92 (dd, 1H), 8.70 (d, 1H),8.21-8.17 (m, 4H), 7.84 (dd, 1H), 7.63 (s, 1H), 3.54-3.47 (m, 1H),3.33-3.26 (m, 1H), 3.16-3.09 (m, 3H), 1.91-1.83 (m, 1H), 1.65-1.56 (m,1H), 1.42-1.32 (m, 2H); LCMS (APCI+) m/z 371 (M+H)+, Retention time=1.95minutes (Method 2).

Example 9

(R)—N-(5-Chloro-4-(3-(isopropylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

(R)—N-(5-Chloro-4-(3-(isopropylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (30 mg, 64% yield) was prepared as described in Example 6,using propan-2-one (104 mg, 1.80 mmol) and substituting(R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (43 mg, 0.089 mmol) for(S)—N-(4-(3-(aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride. ¹H NMR (400 MHz, D₂O) δ 9.20-9.19 (m, 1H), 8.88-8.83 (m,2H), 8.17 (s, 1H), 8.05-7.80 (m, 1H), 7.44-7.43 (m, 11H), 3.86-3.73 (m,1H), 3.50-3.44 (m, 1H), 3.41-3.31 (m, 2H), 3.18-3.10 (m, 1H), 3.06-2.98(m, 1H), 2.04-1.95 (m, 1H), 1.69-1.61 (m, 1H), 1.58-1.47 (m, 1H),1.35-1.25 (m, 1H), 1.14 (d, 3H), 1.10 (d, 3H); LCMS (APCI+) m/z 413.1(M+H)+, Retention time=2.06 minutes (Method 2).

Example 10

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamide

Step A:N-(5-Chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamide(250 mg, 76% yield) was prepared as described in Example 1, Step 1,substituting 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg,1.1 mmol) for 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine and5-methylnicotinic acid (310 mg, 2.26 mmol) for nicotinic acid. ¹H NMR(400 MHz, (CD₃)₂SO) δ 8.94 (d, 1H), 8.60 (d, 1H), 8.29-8.23 (m, 1H),8.14 (s, 1H), 7.65 (s, 1H), 2.40 (s, 3H); LCMS (APCI+) m/z 305 (M+H)+,Retention time=2.66 minutes (Method 2).

Step B:(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamidehydrochloride (70 mg, 19% yield) was prepared as described in Example 1,Steps J and K, substitutingN-(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamide(230 mg, 0.755 mmol) forN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide and(R)-tert-butyl piperidin-3-ylcarbamate (378 mg, 1.89 mmol) fortert-butyl piperidin-3-ylcarbamate. ¹H NMR (400 MHz, D₂O) δ 8.94 (d,1H), 8.69 (d, 1H), 8.66 (d, 1H), 8.13 (s, 1H), 7.43 (s, 1H), 3.69-3.62(m, 1H), 3.37-3.27 (m, 2H), 3.22-3.14 (m, 1H), 3.09-3.01 (m, 1H), 2.47(s, 3H), 1.92-1.83 (m, 1H), 1.69-1.58 (m, 1H), 1.49-1.31 (m, 2H); LCMS(APCI+) m/z 385.1 (M+H)+, Retention time=2.09 minutes (Method 2).

Example 11

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-chloronicotinamide

Step A:5-Chloro-N-(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(320 mg, 91% yield) was prepared as described in Example 1, Step I,substituting 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg,1.1 mmol) for 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine and5-chloronicotinic acid (357 mg, 2.26 mmol) for nicotinic acid. ¹H NMR(400 MHz, (CD₃)₂SO) δ 9.08 (s, 1H), 8.84 (d, 1H), 8.42 (s, 1H), 8.32 (s,1H), 8.30 (s, 1H); LCMS (APCI+) m/z 326 (M+H)+, Retention time=2.94minutes (Method 2).

Step B:(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-chloronicotinamidehydrochloride (0.13 g, 85% yield) was prepared as described in Example1, Steps J and K, substituting5-chloro-N-(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(0.35 g, 1.1 mmol) forN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide and(R)-tert-butyl piperidin-3-ylcarbamate (0.647 g, 3.23 mmol) for butylpiperidin-3-ylcarbamate. ¹H NMR (400 MHz, D₂O) δ 8.87 (d, 1H), 8.68 (d,1H), 8.35-8.30 (m, 1H), 8.15 (s, 1H), 7.43 (s, 1H), 3.81-3.74 (m, 11H),3.49-3.37 (m, 2H), 3.20-3.13 (m, 1H), 3.11-3.03 (m, 1H), 1.97-1.88 (m,1H), 1.69-1.61 (m, 1H), 1.53-1.44 (m, 1H), 1.42-1.31 (m, 1H); LCMS(APCI+) m/z 405, 407 (M+H)+, Retention time=2.21 minutes (Method 2).

Example 12

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: 4-Chloro-1H-pyrrolo[2,3-b]pyridine (5.0 g, 32.8 mmol) in THF (50mL) was cooled to 0° C., and NaH (1.64 g, 41.0 mmol, 60% oil dispersion)was added. After 15 minutes, triisopropylsilylchloride (“TIPS-Cl”; 6.94mL, 32.8 mmol) was added, and the reaction was stirred at roomtemperature for 1 hour. A saturated ammonium chloride solution (20 mL)was added, and the mixture was extracted with hexanes (40 mL), washedwith brine and dried over sodium sulfate. After removal of the solvent,the residue was purified by chromatography (hexanes) to give4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (10.0 g, 99%yield) as an oil.

Step B: s-BuLi (59.3 mL, 71.2 mmol, 1.4M in cyclohexane) at −78° C. wasadded to 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (10.0g, 32.4 mmol) in THF (100 mL), and the reaction was stirred at −78° C.for 30 minutes. 12 (20.5 g, 80.9 mmol) in THF (50 mL) was added, and thereaction was stirred at −78° C. for 20 minutes. A saturated ammoniumchloride solution (50 mL) and a saturated sodium sulfite solution (50mL) were added, and the mixture was extracted with hexanes (200 mL),washed with brine and dried over sodium sulfate. After removal of thesolvent, the residue was dissolved in THF (50 mL), and TBAF (32.4 mL,32.4 mmol) was added. The reaction was stirred at room temperature for10 minutes, and then water (20 mL) and ethyl acetate (100 mL) wereadded. The organic layer was separated, washed with brine, and driedover sodium sulfate. After removal of the solvent, the residue wassuspended in dichloromethane (“DCM”; 20 mL) and stirred for 10 minutes.The solid formed was collected by filtration to give4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridine (6.6 g, 73% yield) as a solid.

Step C: NaH (0.960 g, 24.0 mmol, 60% dispersion in mineral oil) at 0° C.was added to 4-chloro-5-iodo-1H-pyrrolo[2,3-b]pyridine (5.57 g, 20.0mmol) in dimethylformamide (“DMF”; 40 mL) and stirred at 0° C. for 20minutes. Benzenesulfonyl chloride (2.82 mL, 22.0 mmol) was added, andthe reaction was stirred at room temperature for 2 hours. Water (200 mL)was added and stirred for 10 minutes. The solid formed was collected byfiltration, washed with ether, and dried to give4-chloro-5-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (8.20 g,98% yield).

Step D: A mixture of4-chloro-5-iodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (2.0 g, 4.8mmol), Cu(I)I (0.910 g, 4.78 mmol) and methyl2,2-difluoro-2-(fluorosulfonyl)acetate (2.1 mL, 16.7 mmol) in DMF (10mL) was heated at 100° C. for 3 hours. The reaction was cooled to roomtemperature, diluted with EtOAc (30 mL) and filtered through a plug ofcelite. The filtrate was washed with water (15 mL), brine (15 mL), dried(Na₂SO₄), and concentrated in vacuo. The residue was purified by flashchromatography on silica gel eluting with 1:1 CH₂Cl₂/hexanes to provide4-chloro-1-(phenylsulfonyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine(1.4 g, 81% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 8.80 (s,1H), 8.25 (d, 1H), 8.16 (d, 2H), 7.80-7.76 (m, 1H), 7.69-7.65 (m, 2H),7.07 (d, 1H); LCMS (APCI+) m/z 360.9, 362.9 (M+H)+.

Step E: A solution of 2M LiOH (19.1 mL, 38.2 mmol) was added to asolution of4-chloro-1-(phenylsulfonyl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine(4.59 g, 12.7 mmol) in THF (20 mL), and the reaction was stirred at roomtemperature for 20 hours. The mixture was neutralized to a pH of about 8with saturated potassium hydrogen sulfate and extracted with ethylacetate (50 mL). The organic phase was washed with brine, dried(Na₂SO₄), filtered and concentrated in vacuo to provide4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (2.5 g, 91%yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.54 (br s, 1H), 8.59(s, 1H), 7.82 (d, 1H), 6.71 (d, 1H); LCMS (APCI+) m/z 220.9 (M+H)+.

Step F: 4-Chloro-5-(trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (0.18 g,0.84 mmol) was added slowly to fuming nitric acid (1.68 mL, 33.5 mmol)at 0° C. and stirred for 10 minutes. Ice (20 g) was added, followed bywater (30 mL). The solid formed was collected by filtration to give4-chloro-3-nitro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (0.20 g,90% yield) as a solid.

Step G: SnCl₂ dihydrate (0.85 g, 3.77 mmol) at a temperature of about 0°C. to about 5° C. was added to4-chloro-3-nitro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine (0.20 g,0.75 mmol) in 6M HCl (5 mL). The mixture was stirred at room temperaturefor 2 hours, and was then neutralized to a pH of about 8 with a 6N NaOHsolution. The mixture was extracted with CHCl₃:IPA (3×30 mL; 3:1) anddried over sodium sulfate. After removal of the solvent,4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (0.16 g,89% yield) was isolated as a solid.

Step H: Triethylamine (“TEA”; 0.50 mL, 3.61 mmol) was added to4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (0.17 g,0.72 mmol), nicotinic acid (0.18 g, 1.44 mmol) and BOP-Cl (0.37 g, 1.44mmol) in DCM (10 mL). The mixture was stirred for 30 minutes, and waterwas added (10 mL). The solid formed was collected by filtration, washedwith DCM (10 mL) and dried to giveN-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(80 mg, 0.2 mmol, 32% yield) as a solid.

Step I:N-(4-Chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(80 mg, 0.2 mmol) and (R)-tert-butyl piperdin-3-ylcarbamate (0.14 g,0.70 mmol) in n-BuOH (3 mL) were stirred at 143° C. (bath) for 32 hours.The solvent was removed, and the residue was dissolved in ethyl acetate(20 mL), washed with water (10 mL), brine (10 mL) and dried over sodiumsulfate. After removal of the solvent, the residue was purified by C-18reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column,10-80% CH₃CN/water gradient; 30 CV) to give a solid. This solid wasdissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture wasstirred at room temperature for 30 minutes. The solvent was removed. Theresidue was dissolved in DCM (1 mL) and 2N HCl in ether (2 mL) wasadded. The solid formed was collected by filtration to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (0.047 g, 39% yield) as a solid. ¹H NMR (400 MHz,(CD₃)₂SO) δ 12.43 (d, 1H), 10.54 (s, 1H), 9.42 (d, 1H), 8.98 (dd, 1H),8.88 (d, 1H), 8.53 (s, 1H), 8.25 (br s, 3H), 7.97 (dd, 1H), 7.74 (d,1H), 3.36-3.29 (m, 1H), 3.12-3.05 (m, 2H), 3.04-2.95 (m, 2H), 1.94-1.84(m, 1H), 1.67-1.57 (m, 1H), 1.54-1.42 (m, 1H), 1.33-1.19 (m, 1H); LCMS(APCI+) m/z 405.1 (M+H)+.

Example 13

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (2.00g, 6.84 mmol) in THF (20 mL) was added to s-BuLi (12.5 mL, 15.0 mmol,1.4M in cyclohexane) at −78° C. for 30 minutes.N-Fluoro-N-(phenylsulfonyl)benzenesulfonamide (5.39 g, 17.1 mmol) in THF(15 mL) was added, and it was stirred at −78° C. for 20 minutes. Asaturated ammonium chloride solution (20 mL) was added and extractedwith hexanes (50 mL), washed with brine, and dried over sodium sulfate.After removal of the solvent, the residue was dissolved in THF (10 mL),and TBAF (6.84 mL, 6.84 mmol) in THF (6.84 mL, 6.84 mmol) was added. Thereaction was stirred at room temperature for 10 minutes, and water (20mL) and ethyl acetate (30 mL) were added. The organic layer wasseparated, washed with brine and dried over sodium sulfate. Afterremoval of the solvent, the residue was purified by chromatography(ethyl acetate) to give 4,5-difluoro-1H-pyrrolo[2,3-b]pyridine (0.63 g,60% yield) as a solid. LCMS (APCI+) m/z 155.1 (M+H)+.

Step B: 4,5-Difluoro-1H-pyrrolo[2,3-b]pyridine (0.63 g, 4.09 mmol) wasadded slowly to fuming nitric acid (8.18 mL, 164 mmol) at 0° C. andstirred slowly for 5 minutes. Ice (20 g) was added followed by water (40mL). The solid formed was collected by filtration to give4,5-difluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (0.65 g, 80% yield) as asolid.

Step C: SnCl₂ dihydrate (3.68 g, 16.3 mmol) at a temperature of about 0°C. to about 5° C. was added to4,5-difluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (0.65 g, 3.26 mmol) in 6MHCl (5 mL). The mixture was stirred at room temperature for 30 minutes.The mixture was neutralized to a pH of about 8 with a 6N NaOH solution.The mixture was extracted with CHCl₃:IPA (3×30 mL; 3:1) and dried oversodium sulfate. After removal of the solvent,4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.45 g, 2.66 mmol, 81%yield) was isolated as a solid.

Step D: Nicotinoyl chloride hydrochloride (0.70 g, 3.90 mmol) was addedto 4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.22 g, 1.30 mmol) inpyridine (5 mL). The reaction was stirred at room temperature for 10minutes, and then the pyridine was removed. THF (5 mL) and 2N LiOH (3mL) were added, and the reaction was stirred for 20 minutes. The THF wasremoved, and water (20 mL) was added. The solid formed was collected byfiltration and dried to giveN-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.33 g, 92%yield) as a solid.

Step E: N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (0.21g, 0.77 mmol), (R)-tert-butyl piperdin-3-ylcarbamate (0.31 g, 1.53 mmol)and DIEA (0.13 mL, 0.77 mmol) in n-BuOH (3 mL) were stirred at 143° C.(bath) for 24 hours. The solvent was removed. The residue was dissolvedin ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), anddried over sodium sulfate. After removal of the solvent, the residue waspurified by C-18 reverse phase flash chromatography (Biotage SP4 unit,C-18 25M column, 10-80% CH₃CN/water gradient; 30 CV) to give a solid.This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. Themixture was stirred at room temperature for 1 hour. The solvent wasremoved. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3mL) was added. The solid formed was collected by filtration to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (0.23 g, 66% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.89 (d, 1H), 10.38 (s, 1H), 9.33 (d, 1H), 8.88 (dd, 1H), 8.64 (dt,1H), 8.18 (s, 1H), 8.17 (br s, 3H), 7.76 (dd, 1H), 7.60 (d, 1H),3.64-3.56 (m, 1H), 3.25-3.17 (m, 2H), 3.16-3.07 (m, 1H), 3.04-2.95 (m,1H), 1.87-1.75 (m, 1H), 1.62-1.52 (m, 1H), 1.48-1.38 (m, 1H), 1.35-1.22(m, 1H); LCMS (APCI+) m/z 355.1 (M+H)+.

Example 14

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: Triethylamine (0.130 mL, 0.931 mmol), Boc₂O (81 mg, 0.373 mmol),and 4-dimethylaminopyridine (“DMAP”; 19 mg, 0.155 mmol) were added to asolution of (R)-tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(160 mg, 0.31 mmol, Example 1A) in CH₂Cl₂ (5 mL) at room temperature,and the reaction was stirred for 30 minutes. The reaction was thenpoured into water and extracted with CH₂Cl₂. The organic phase wasseparated, dried (Na₂SO₄), filtered, and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel eluting with1.6% CH₃OH/CH₂Cl₂ to provide (R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(170 mg, 89% yield). LCMS (APCI+) m/z 615, 617 (M+H)+, Retentiontime=4.08 minutes (Method 2).

Step B: A mixture of (R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(170 mg, 0.276 mmol), cyclopropylboronic acid (95 mg, 1.10 mmol), K₃PO₄(205 mg, 0.967 mmol), Pd(OAc)₂ (6.20 mg, 0.0276 mmol), andtricyclohexylphosphine (9.3 mg, 0.033 mmol) in toluene/water (10:1mixture, 4.4 mL) was degassed under argon and heated at 80° C. for 15hours. The reaction mixture was then allowed to cool to roomtemperature. The mixture was poured into water and extracted withCH₂Cl₂. The organic phase was dried (Na₂SO₄), filtered and concentratedin vacuo. The residue was purified by C-18 reverse phase flashchromatography (Biotage SP4 unit, C-18 25M column, 5 to 95% CH₃CN/watergradient; 30 CV) to provide (R)-tert-butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-cyclopropyl-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(81 mg, 51% yield). LCMS (APCI+) m/z 577.2 (M+H)+, Retention time=4.01minutes (Method 2).

Step C: (R)-tert-Butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-cyclopropyl-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(81 mg, 0.14 mmol) was treated with TFA followed by 2M HCl in ether asdescribed in Example 1, Step K, to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (33 mg, 48% yield). ¹H NMR (400 MHz, D₂O) δ 9.16 (d, 1H),8.82 (dd, 1H), 8.72 (dt, 1H), 7.95 (s, 1H), 7.92 (dd, 1H), 7.41 (s, 1H),3.98-3.93 (m, 1H), 3.61-3.53 (m, 1H), 3.32-3.25 (m, 2H), 3.15-3.06 (m,1H), 1.96-1.85 (m, 2H), 1.64-1.56 (m, 1H), 1.52-1.41 (m, 1H), 1.39-1.27(m, 1H), 0.98-0.92 (m, 2H), 0.70-0.61 (m, 2H); LCMS (APCI+) m/z 377.2(M+H)+, Retention time=2.12 minutes (Method 2).

Example 15

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

Step A: Isobutyric acid (306 mg, 3.48 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (885 mg, 3.48 mmol) andtriethylamine (880 mg, 8.69 mmol) were added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (400 mg, 1.74 mmol) inDCM (200 mL). The reaction was stirred at room temperature for 1 hour,and then 3M aqueous LiOH (4 mL) was added. The reaction as stirred for 1hour, and then saturated aqueous Na₂CO₃ was added (200 mL). The aqueousphase was extracted 3 times with DCM (200 mL). Then the combined organicphases were dried over MgSO₄ and concentrated to dryness. The residuewas purified by C-18 reverse phase flash chromatography (Biotage SP4unit, C-18 25M column, 20-100% CH₃CN/water gradient; 20 CV) to yieldN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (158 mg,30% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.03 (br s, 1H),9.40 (s, 1H), 8.34 (d, 1H), 7.56 (d, 1H), 2.69-2.62 (m, 1H), 1.12 (d,6H); LCMS (APCI+) m/z 299.9, 301.9 (M+H)+, Retention time=3.02 minutes(Method 3).

Step B: (R)-tert-Butyl piperidin-3-ylcarbamate (327 mg, 1.63 mmol) wasadded to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide(140 mg) in n-BuOH (3 mL), and the reaction was stirred at 160° C. for24 hours in a sealed tube. The reaction was concentrated to dryness.Then the residue was purified by C-18 reverse phase flash chromatography(Biotage SP4 unit, C-18 25M column, 10-90% gradient CH₃CN/watergradient; 30 CV) to yield (R)-tert-butyl1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3ylcarbamate(105 mg, 47% yield) as a solid.

Step C: (R)-tert-Butyl1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3ylcarbamate(90 mg, 0.19 mmol) was dissolved in TFA (5 mL) and stirred for 30minutes at room temperature. The reaction was concentrated to drynessand dissolved in a minimal amount of methanol. The solution was addeddropwise to a stirred solution of 4N HCl in dioxane. The resulting solidwas filtered and dried under high vacuum to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (65 mg, 91% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.78 (d, 1H), 9.26 (s, 1H), 8.26 (br s, 3H), 8.24 (s, 1H), 7.61 (brs, 1H), 3.52-3.27 (m, 4H), 3.12-3.05 (m, 1H), 2.69-2.61 (m, 1H),2.17-2.10 (m, 1H), 1.91-1.83 (m, 1H), 1.74-1.62 (m, 1H), 1.56-1.45 (m,1H), 1.16 (d, 6H). LCMS (ACPI+) m/z 380, 382 (M)+, Retention time=1.84minutes (Method 1).

Example 16

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide

Step A: (R)-tert-Butyl piperidin-3-ylcarbamate (162 mg, 0.81 mmol) wasadded to N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamide (90mg, 0.27 mmol, Example 7, Step A) in n-BuOH (3 mL), and the reaction wasstirred at 160° C. for 24 hours in a sealed tube. The reaction wasconcentrated to dryness. The residue was then purified by chromatography(SP4, C-18 25M+ column, 10-90% CH₃CN/water gradient, 30 CV) to yield(R)-tert-butyl1-(3-benzamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(61 mg, 44% yield) as a solid.

Step B: (R)-tert-Butyl1-(3-benzamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamatewas dissolved in TFA (5 mL) and stirred for 30 minutes at roomtemperature. The reaction was concentrated to dryness and then dissolvedin a minimal amount of methanol. The solution was added dropwise to astirred solution of 2N HCl in ether. The resulting solid was filteredand dried under high vacuum to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)benzamidehydrochloride (26 mg, 72% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.92 (d, 1H), 9.92 (s, 1H), 8.27 (s, 1H), 8.12 (br s, 3H), 8.03 (d,2H), 7.70 (br s, 1H), 7.64-7.55 (m, 3H), 3.50-3.40 (m, 2H), 3.30-3.19(m, 2H), 3.13-3.03 (m, 1H), 1.94-1.83 (m, 1H), 1.70-1.61 (m, 1H),1.51-1.25 (m, 2H); LCMS (APCI+) m/z 414, 416 (M+H)+, Retention time=2.25minutes (Method 1).

Example 17

(R)—N-(5-Bromo-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: (R)-tert-Butyl methyl(piperidin-3-yl)carbamate (384 mg, 1.79mmol) was added toN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (200 mg,0.597 mmol, Example 1, Step I) in n-BuOH (3 mL), and the reaction wasstirred at 160° C. for 24 hours in a sealed tube. The reaction wasconcentrated to dryness. The residue was then purified by chromatography(Biotage SP4, C-18 25M+ column, 10-90% CH₃CN/water gradient, 30 CV) toyield (R)-tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamateas a solid.

Step B: (R)-tert-Butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(51 mg, 0.096 mmol) was dissolved in TFA (5 mL) and stirred for 30minutes at room temperature. The reaction was concentrated to drynessand then dissolved in a minimal amount of methanol. The solution wasadded dropwise to a stirred solution of 4N HCl in dioxane. The resultingsolid was filtered and dried under high vacuum to yield(R)—N-(5-bromo-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (33 mg, 80% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.99 (d, 1H), 9.30 (d, 1H), 8.99-8.86 (m, 3H), 8.58 (d, 1H), 8.28 (s,1H), 7.76 (dd, 1H), 7.63 (br s, 1H), 3.59-3.49 (m, 1H), 3.35-3.05 (m,4H), 2.49 (s, 3H), 2.06-1.90 (m, 1H), 1.71-1.62 (m, 1H), 1.48-1.25 (m,2H); LCMS (APCI+) m/z 431.0 (M+H)+, Retention time=2.02 minutes (Method1).

Example 18

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbenzamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.250 g, 1.09mmol), 3-methylbenzoic acid (311 mg, 2.28 mmol), BOP-Cl (581 mg, 2.28mmol), and triethylamine (0.757 mL, 5.43 mmol) in DCM (5 mL) werestirred at room temperature for 30 minutes. 3M LiOH (3 mL) was thenadded. The reaction was stirred for an additional 10 minutes and thenpoured into water. The mixture was then filtered, washed with DCM,washed with 10:1 DCM:MeOH and dried to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbenzamide(210 mg, 55.5% yield) as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbenzamide(210 mg, 0.60 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (360 mg,1.8 mmol) in n-BuOH (3 mL) was stirred at 155° C. in a sealed tube. Thereaction was then cooled to room temperature and concentrated todryness. The crude residue was purified by reverse phase HPLC to give(R)-tert-butyl1-(5-bromo-3-(3-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(150 mg, 47% yield).

Step C: (R)-tert-Butyl1-(5-bromo-3-(3-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(123 mg, 0.233 mmol) in DCM (3 mL) at room temperature was treated withTFA (1 mL), and the reaction was stirred for 1 hour. The reactionmixture was then concentrated to dryness. The resulting residue wasdissolved in minimal DCM and added to a stirring solution of 1M HCl inether. The solid formed was filtered, washed with ether and dried togive(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbenzamidehydrochloride (0.102 g, 87.4% yield). ¹H NMR (400 MHz, D₂O) δ 8.02 (s,1H), 7.64 (s, 1H), 7.62-7.52 (m, 1H), 7.42-7.38 (m, 3H), 3.49-3.42 (m,1H), 3.27-3.18 (m, 2H), 3.17-3.06 (m, 2H), 2.29 (s, 3H), 1.81-1.71 (m,1H), 1.68-1.57 (m, 1H), 1.49-1.26 (m, 2H); LCMS (APCI+) m/z 428, 430(M+H)+, Retention time=2.68 minutes (Method 2).

Example 19

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methylnicotinamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(250 mg, 1.09 mmol), 6-methylnicotinic acid (313 mg, 2.28 mmol), BOP-Cl(581 mg, 2.28 mmol), and triethylamine (0.757 mL, 5.43 mmol) in DCM (5mL) was stirred at room temperature for 30 minutes. 3M LiOH (3 mL) wasthen added. The reaction was stirred for an additional 10 minutes andthen poured into water. The mixture was then filtered, washed with DCM,washed with 10:1 DCM:MeOH and dried to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methylnicotinamide(260 g, 68.5% yield) as a solid

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methylnicotinamide(260 mg, 0.745 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (447 mg,2.23 mmol) in n-BuOH (3 mL) was heated to 155° C. in a sealed tube. Thereaction was then cooled to room temperature and concentrated todryness. The crude residue was purified by reverse phase HPLC to give(R)-tert-butyl1-(5-bromo-3-(6-methylnicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(12 mg, 3% yield).

Step C: (R)-tert-Butyl1-(5-bromo-3-(6-methylnicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(12 mg, 0.023 mmol) in DCM (3 mL) at room temperature was treated withTFA (1 mL). The reaction was stirred for 1 hour and then concentrated todryness. The resulting residue was dissolved in a minimal amount of DCMand then added to a stirring solution of 1M HCl in ether. The resultingsolid was filtered, washed with ether and dried to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methylnicotinamidehydrochloride (0.004 g, 33% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ9.02-8.99 (m, 1H), 8.65-8.61 (m, 1H), 8.23 (d, 1H), 7.80 (d, 1H), 7.40(d, 1H), 3.52-3.46 (m, 1H), 3.36-3.26 (m, 1H), 3.25-3.17 (m 1H),3.15-3.06 (m 2H), 2.67 (s, 3H), 1.84-1.76 (m, 1H), 1.71-1.61 (m, 1H),1.46-1.31 (m, 2H); LCMS (APCI+) m/z 429, 431 (M+H)+, Retention time=2.25minutes (Method 2).

Example 20

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamide

Step A: 5-Methylnicotinic acid (477 mg, 3.48 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (885 mg, 3.48 mmol) andtriethylamine (880 mg, 8.69 mmol) were added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (400 mg, 1.74 mmol) inDCM (200 mL). The reaction was stirred at room temperature for 1 hour,and then 3M aqueous LiOH (4 mL) was added. The reaction was stirred for1 hour, and then saturated aqueous Na₂CO₃ was added (200 mL). Theaqueous phase was extracted once with DCM (200 mL), and then the aqueousphase was filtered. The filtered cake was dried to yieldN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamide(228 mg, 37.6% yield) as a solid.

Step B: (R)-tert-Butyl piperidin-3-ylcarbamate (172 mg, 0.859 mmol) wasadded toN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamide(100 mg, 0.286 mmol) in n-BuOH (3 mL), and the reaction was stirred at160° C. for 24 hours in a sealed tube. The reaction was concentrated todryness, and then the residue was purified by chromatography (SP4, 25M,water/ACN 90/10 to 10/90, 30CV) to yield (R)-tert-butyl1-(5-bromo-3-(5-methylnicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(47 mg, 31.0% yield) as a solid.

Step C: (R)-tert-Butyl1-(5-bromo-3-(5-methylnicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(40 mg, 0.076 mmol) was dissolved in TFA (5 mL) and stirred for 30minutes at room temperature. The reaction was concentrated to drynessand then dissolved in a minimal amount of methanol. The solution wasadded dropwise to a stirred solution of 4N HCl in dioxane. The resultingsolid was filtered and dried under high vacuum to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylnicotinamidehydrochloride (24 mg, 74% yield) as a solid ¹H NMR (400 MHz, (CD₃)₂SO) δ10.29 (br s, 1H), 9.16 (s, 11H), 8.79 (s, 1H), 8.52 (s, 1H), 8.27 (s,1H), 8.15 (br s, 3H), 7.63 (s, 1H), 3.48-3.27 (m, 2H), 3.26-3.02 (m,3H), 2.50 (s, 3H), 1.96-1.84 (m, 1H), 1.69-1.59 (m, 1H), 1.51-1.28 (m,2H); LCMS (APCI+) m/z 429, 431 (M+H)+, Retention time=1.90 min (Method1).

Example 21

N-(5-Bromo-4-(tetrahydro-1H-pyrrolo[2,3-c]pyridin-6(2H,7H,7aH)-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: 1H-Pyrrolo[2,3-c]pyridine (2.50 g, 21.2 mmol) and triethylamine(3.24 mL, 23.3 mmol) were placed in DCM (25 mL) at room temperature.di-tert-Butyl dicarbonate (4.85 g, 22.2 mmol) was then added, and thereaction stirred for 30 minutes. The reaction was then poured into waterand extracted with DCM. The organic fraction was dried, filtered, andconcentrated. The crude was purified by column chromatography on silicagel (500:3 DCM:MeOH) to give tert-butyl1H-pyrrolo[2,3-c]pyridine-1-carboxylate (4.4 g, 95.3% yield).

Step B: tert-Butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.0 g, 4.58mmol) and PtO₂ (0.208 g, 0.916 mmol) were placed in 1:1 EtOH:AcOH (10mL) and shaken at 50 PSI under H₂ for 8 hours. The reaction was thenconcentrated. The crude oil was dissolved in DCM, poured into saturatedNa₂CO₃ and extracted into DCM. The organic fraction was dried, filtered,and concentrated to give the product as an oil, tert-butyloctahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.99 g, 95.5% yield).

Step C:N-(5-Bromo-4-(tetrahydro-1H-pyrrolo[2,3-c]pyridin-6(2H,7H,7aH)-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(0.060 g, 79% yield) was prepared as described in Example 1, Steps J andK, using N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(0.250 g, 0.746 mmol) and substituting tert-butyloctahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (0.506 g, 2.24 mmol)for tert-butyl piperidin-3-ylcarbamate. ¹H NMR (400 MHz, D₂O) δ 9.14 (d,1H), 8.82 (dd, 1H), 8.71 (d, 1H), 8.28 (s, 1H), 7.92 (dd, 1H), 7.43 (s,1H), 3.68-3.63 (m, 1H), 3.54-3.50 (m, 2H), 3.42-3.33 (m, 2H), 3.31-3.21(m, 2H), 3.09-3.01 (m 1H), 2.27-2.21 (m, 1H), 1.95-1.85 (m, 1H),1.74-1.65 (m, 2H); LCMS (APCI+) m/z 441, 443 (M+H)+, Retention time=2.04minutes (Method 2).

Example 22

N-(5-Bromo-4-(3-(methylamino)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg,0.30 mmol), tert-butyl methyl(pyrrolidin-3-yl)carbamate (240 mg, 1.19mmol) and DIEA (0.0520 mL, 0.30 mmol) in n-BuOH (3 mL) were stirred at143° C. (bath) for 24 hours. The solvent was removed. The residue wasdissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10mL), and dried over sodium sulfate. After removal of the solvent, theresidue was purified by chromatography (ethyl acetate:MeOH, 10:1) togive a solid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL)was added. The mixture was stirred at room temperature for 1 hour. Thesolvent was removed. The residue was dissolved in DCM (1 mL) and 2N HClin ether (3 mL) was added. The solid formed was collected by filtrationto giveN-(5-Bromo-4-(3-(methylamino)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(93 mg, 59% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ 9.14 (d, 1H),8.83 (dd, 1H), 8.71 (dt, 1H), 8.23 (s, 1H), 7.98 (dd, 1H), 7.44 (s, 1H),4.02-3.96 (m, 1H), 3.76-3.68 (m, 3H), 3.65-3.59 (m, 1H), 2.22-2.13 (m,1H), 1.93-1.84 (m, 1H); LCMS (APCI+) m/z 415, 417 (M+H)+.

Example 23

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Step A: TEA (0.61 mL, 4.35 mmol) was added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.20 g, 0.87 mmol,Example 1, Step H), 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid(0.17 g, 1.13 mmol) and BOP-Cl (0.33 g, 1.30 mmol) in DCM (10 mL). Thereaction was stirred at room temperature for 1 hour, and then a LiOHsolution (3 mL, 2N) was added. The mixture was stirred for 30 minutes,and water (10 mL) was added. The solid formed was collected byfiltration, washed with DCM (10 mL) and dried to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide(0.22 g, 69% yield) as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide(0.22 g, 0.602 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.362g, 1.81 mmol) in n-BuOH (2 mL) were stirred at 143° C. (bath) for 24hours. The solvent was removed, and the residue was dissolved in ethylacetate (20 mL), washed with water (10 mL), brine (10 mL) and dried oversodium sulfate. After removal of the solvent, the residue was purifiedby C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25Mcolumn, 10-80% CH₃CN/water gradient; 30 CV) to give a solid. This solidwas dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture wasstirred at room temperature for 1 hour. The solvent was removed. Theresidue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) wasadded. The solid formed was collected by filtration to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamidehydrochloride (0.113 g, 36% yield) as a solid. ¹H NMR (400 MHz,(CD₃)₂SO) δ 11.94 (s, 1H), 9.74 (s, 1H), 8.62 (s, 1H), 8.25 (s, 1H),8.15 (br s, 3H), 8.06 (d, 1H), 7.51 (s, 1H), 6.49 (d, 1H), 3.44 (m, 1H),3.32 (m, 1H), 3.20 (m, 2H), 3.07 (m, 1H), 1.93 (m, 1H), 1.66 (m, 1H),1.49 (m, 1H), 1.35 (m, 1H); LCMS (APCI+) m/z 445 (M+H)+.

Example 24

N-(5-Bromo-4-(3-(pyridin-2-yl)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg,0.3 mmol, Example 1, Step 1) in n-BuOH (3 mL) and2-(pyrrolidin-3-yl)pyridine (133 mg, 0.9 mmol) were heated to 160° C. ina sealed tube for 48 hours. After cooling down, the reaction wasconcentrated to dryness, and the residue purified by C-18 reverse phaseflash chromatography (Biotage SP4 unit, C-18 25M column, 10-90%CH₃CN/water gradient; 30 CV) to yieldN-(5-bromo-4-(3-(pyridin-2-yl)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(29 mg) as a solid. This solid was dissolved in MeOH (1 mL), and thenthe solution was added dropwise to a 4N HCl solution in dioxane. Theresulting solid was collected and dried to yieldN-(5-bromo-4-(3-(pyridin-2-yl)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (35 mg, 25% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 12.07 (d, 1H), 10.52 (s, 1H), 9.30 (d, 1H), 8.94-8.91 (m, 1H),8.72-8.66 (m, 2H), 8.39-8.33 (m, 2H), 7.92-7.76 (m, 3H), 7.71 (d, 1H),7.20 (br s, 2H), 4.06-3.95 (m, 2H), 3.80-3.67 (m, 3H), 2.48-2.40 (m,1H), 2.23-2.11 (m, 1H). LCMS (APCI+) m/z 463, 465 (M+H)+, Retentiontime=2.78 minutes (Method 1).

Example 25

N-(4-(3-Aminoazetidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(100 mg, 0.3 mmol, Example 1, Step 1) in n-BuOH (3 mL) and tert-butylazetidin-3-ylcarbamate (154 mg, 0.9 mmol) were heated to 110° C. in asealed tube for 24 hours. After cooling down, the reaction wasconcentrated to dryness, and the residue purified by C-18 reverse phaseflash chromatography (Biotage SP4 unit, C-18 25M column, 10-90%CH₃CN/water gradient; 30 CV) to yield tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3-ylcarbamate(54 mg, 37% yield) as a solid.

Step B: tert-Butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)azetidin-3-ylcarbamate(54 mg, 0.11 mmol) was stirred in TFA (3 mL) for 30 minutes, and thenthe reaction was concentrated to dryness. The residue was dissolved in aminimal amount of methanol, and then it was added dropwise to a 4N HCldioxane solution. The resulting solid was collected and rinsed with DCMand dried under high vacuum to yieldN-(4-(3-aminoazetidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (41 mg, 96% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 12.45 (d, 1H), 10.70 (s, 1H), 8.90 (dd, 1H), 8.68-8.64 (m, 1H), 8.57(br s, 2H), 8.26 (s, 1H), 7.80 (dd, 1H), 7.40 (d, 1H), 5.76 (br s, 3H),4.85-4.75 (m, 2H), 4.56-4.50 (m, 2H), 4.00-3.90 (m, 1H). LCMS (APCI+)m/z 387, 389 (M+H)+, Retention time=1.63 minutes (Method 1).

Example 16

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-fluorobenzamide

Step A: 4-Fluorobenzoyl chloride (0.15 mL, 1.30 mmol) was added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol,Example 1, Step H) in pyridine (5 mL). The reaction was stirred at roomtemperature for 10 minutes, and then the pyridine was removed. THF (5mL) and 2N LiOH (3 mL) were added and stirred for 20 minutes. The THFwas removed, and water (20 mL) was added. The solid formed was collectedby filtration and dried to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-fluorobenzamide(0.24 g, 77% yield) as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-fluorobenzamide(0.24 g, 0.67 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.40 g,2.01 mmol) in n-BuOH (2 mL) were stirred at 143° C. (bath) for 24 hours.The solvent was removed, and the residue was dissolved in ethyl acetate(20 mL), washed with water (10 mL), brine (10 mL) and dried over sodiumsulfate. After removal of the solvent, the residue was purified by C-18reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column,20-80% CH₃CN/water gradient; 30 CV) to give a solid. The solid wasdissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture wasstirred at room temperature for 1 hour. The solvent was removed. Theresidue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) wasadded. The solid formed was collected by filtration to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-fluorobenzamidehydrochloride (0.14 g, 41% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.94 (s, 1H), 9.95 (s, 1H), 8.26 (s, 1H), 8.17-8.-9 (m, 6H), 7.65 (brs, 1H), 7.42 (t, 2H), 3.43-3.35 (m, 2H), 3.25-3.15 (m, 2H), 3.10-3.04(m, 1H), 1.92-1.85 (m, 1H), 1.66-1.59 (m, 1H), 1.46-1.28 (m, 2H); LCMS(APCI+) m/z 432 (M+H)+.

Example 27

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)pivalamide

Step A: Pivaloyl chloride (0.12 mL, 0.98 mmol) was added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.15 g, 0.65 mmol) inpyridine (5 mL). The reaction was stirred at room temperature for 10minutes, and then the pyridine was removed. THF (5 mL) and 2N LiOH (3mL) were added and stirred for 20 minutes. The THF was removed in vacuo,and water (20 mL) was added to the aqueous residue. The solid formed wascollected by filtration and dried to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pivalamide (0.128 g,62% yield) as a solid.

Step B: N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pivalamide(0.128 g, 0.407 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.245g, 1.22 mmol) in n-BuOH (2 mL) were stirred at 143° C. (bath) for 24hours. The solvent was removed, and the residue was dissolved in ethylacetate (20 mL), washed with water (10 mL), brine (10 mL) and dried oversodium sulfate. After removal of the solvent, the residue was purifiedby C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25Mcolumn, 30-80% CH₃CN/water gradient; 30 CV) to give a solid. The solidwas dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture wasstirred at room temperature for 1 hour. The solvent was removed. Theresidue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) wasadded. The solid formed was collected by filtration to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)pivalamidehydrochloride (66 mg, 32% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.78 (s, 1H), 9.03 (s, 1H), 8.25 (s, 1H), 8.18-8.07 (m, 3H),3.49-3.31 (4H), 3.10-3.03 (m, 1H), 2.17-2.07 (m, 1H), 1.93-1.85 (m, 1H),1.77-1.65 (m, 1H), 1.55-2.42 (m, 1H), 1.28 (s, 9H); LCMS (APCI+) m/z 394(M+H)+.

Example 28

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.200 g,0.869 mmol, Example 1, Step H), pyrazine-2-carboxylic acid (0.227 g,1.83 mmol), BOP-Cl (0.465 g, 1.83 mmol), and triethylamine (0.606 ml,4.35 mmol) were placed in DCM (5 mL) and stirred at room temperature for30 minutes. 3M LiOH (3 mL) was then added, and the reaction was stirredfor an additional 10 minutes and then poured into water. The mixture wasthen filtered, washed with DCM, and then washed with 10:1 DCM:MeOH anddried to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide(0.180 g, 61% yield) as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide(0.180 g, 0.536 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.322g, 1.61 mmol) were placed in n-BuOH (2 mL) and heated to 155° C. in asealed tube. The reaction was then cooled to room temperature andconcentrated to dryness. The resulting residue was purified by reversephase HPLC (5 to 95% ACN in water, Gilson system) to give the product,(R)-tert-butyl1-(5-bromo-3-(pyrazine-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.105 g, 38% yield).

Step C: (R)-tert-Butyl1-(5-bromo-3-(pyrazine-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.060 g, 0.12 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added, and the reaction was stirred at room temperaturefor 1 hour and then concentrated to dryness. The resulting residue waspurified by reverse phase HPLC (0 to 50% ACN in water, Gilson system).The resulting product was then dissolved in minimal DCM (with MeOH toaid solubility) and added to a stirring solution of 1M HCl in ether. Theresulting solid was filtered, washed with ether and dried to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamidehydrochloride (0.019 g, 33% yield). ¹H NMR (400 MHz, D₂O) δ 8.69 (s,1H), 8.57-8.56 (m, 1H), 8.50 (s, 1H), 8.04 (s, 1H), 7.60 (s, 1H),3.70-3.62 (m, 1H), 3.55-3.50 (m, 1H), 3.42-3.39 (m, 1H), 3.31-3.29 (m,1H), 2.83-2.80 (m, 1H), 2.19-2.16 (m, 1H), 1.92-1.89 (m, 1H), 1.73-1.69(m, 1H), 1.49-1.47 (m, 1H); LCMS (APCI+) m/z 416, 418 (M+H)+.

Example 29

(R)—N-(4-(3-Aminopiperin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

Step A: A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol) in pyridine (5 mL) at 0° C. was treated dropwisewith cyclopropanecarbonyl chloride (118.3 μL, 1.304 mmol). The mixturewas stirred at 0° C. for 60 minutes, and then the pyridine was removedin vacuo. The residue obtained was dissolved in THF (10 mL) and treatedwith lithium hydroxide hydrate (109.5 mg, 2.61 mmol) in water (1 mL).After 30 minutes, the THF was removed under reduced pressure, and water(5 mL) was added to the residue. The solid formed was filtered, washedwith additional water and dried to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide(165 mg, 64% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.03 (brs, 1H), 9.76 (s, 1H), 8.34 (d, 1H), 7.59 (s, 1H), 1.93-1.86 (m, 1H),0.783 (d, 4H); LCMS (APCI+) m/z 298, 300 (M+H)+, Retention time=2.71 min(Method 2).

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide(160 mg, 0.537 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (537 mg,2.68 mmol) were processed as described in Example 1, Step J. The crudematerial was purified by C-18 reverse phase flash chromatography(Biotage SP4 unit, C-18 25M column, 5-80% CH₃CN/water gradient; 25 CV)to provide (R)-tert-butyl1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(120 mg, 47% yield) as solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.57 (d,1H), 9.61 (s, 1H), 8.14 (s, 1H), 7.52 (br s, 1H), 6.85 (br s, 1H),3.61-3.48 (m, 1H), 3.25-3.13 (m, 3H), 3.09-3.01 (m, 1H), 1.87-1.80 (m,1H), 1.77-1.65 (m, 3H), 1.45-1.32 (m, 1H), 1.29 (s, 9H), 0.77 (d, 4H):LCMS (APCI+) m/z 478, 480 (M+H)+, Retention time=3.59 minutes (Method2).

Step C: (R)-tert-Butyl1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(110 mg, 0.230 mmol) in TFA (5 mL) was stirred at room temperature for30 minutes, and the TFA was removed in vacuo. The oily residue obtainedwas dissolved in CH₂Cl₂ (1 mL), and 2M HCl in Et₂O was added. Themixture was stirred at ambient temperature for 30 minutes. The solidformed was filtered and triturated with CH₃CN to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (70 mg, 67% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.82 (s,1H), 9.65 (s, 1H), 8.26 (br s, 3H), 8.22 (s, 1H), 7.47 (s, 1H),3.46-3.40 (m, 3H), 3.31-3.23 (m, 1H), 3.12-3.06 (m, 1H), 2.15-2.09 (m,1H), 1.87-1.80 (m, 2H), 1.76-1.69 (m, 1H), 1.53-1.43 (m, 1H), 0.83-0.81(m, 4H); LCMS (APCI+) m/z 378.8, 379.9 (M+H)+, Retention time 2.18minutes (Method 2).

Example 30

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869mmol, Example 1, Step H) and cyclopentanecarbonyl chloride (173 mg, 1.30mmol) were processed as described in Example 29, Step A to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide(210 mg, 74% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.04 (br s, 1H), 8.34(d, 1H), 7.56 (s, 1H), 2.88-2.80 (m, 1H), 1.89-1.81 (m, 2H), 1.77-1.64(m, 4H), 1.57-1.53 (m, 2H); LCMS (APCI+) m/z 326, 327.9 (M+H)+,Retention time=3.18 minutes (Method 2).

Step B: A solution ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide(205 mg, 0.629 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butylpiperidin-3-ylcarbamate (629 mg, 3.14 mmol) and stirred at 160° C. for18 hours in a sealed tube. The solvent was removed in vacuo, and theresidue was dissolved in EtOAc (50 mL) and washed with water (2×10 mL).The organic layer was dried (MgSO₄), filtered, and concentrated invacuo. The residue was purified by C-18 reverse phase flashchromatography (Biotage SP4 unit, C-18 25M column, 5-80% CH₃CN/watergradient; 25 CV) to yield a solid, which was crystallized from CH₃CN toprovide (R)-tert-butyl1-(5-bromo-3-(cyclopentanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(70 mg, 22% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.56 (s,1H), 9.36 (s, 1H), 8.14 (s, 1H), 7.64 (br s, 1H), 6.90 (br s, 1H),3.56-3.47 (m, 1H), 3.20-3.11 (m, 2H), 3.04-2.97 (m, 1H), 2.81-2.74 (m,1H), 1.91-1.80 (m, 4H), 1.78-1.70 (m, 3H), 1.67-1.59 (m, 3H), 1.55-1.50(m, 2H), 1.42-1.34 (m, 1H); LCMS (APCI+) m/z 407.9 [(M-Boc)+H]+,Retention time=4.03 minutes (Method 2).

Step C: A solution of (R)-tert-butyl1-(5-bromo-3-(cyclopentanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(65 mg, 0.13 mmol) in neat TFA (5 mL) was stirred at room temperaturefor 20 minutes. TFA was then removed in vacuo, and the residue wasevaporated from CH₂Cl₂ (10 mL). The oily residue obtained was dissolvedin CH₂Cl₂ (0.5 mL) and treated with 2M HCl in Et₂O. After 30 minutes atroom temperature, the solid formed was filtered, washed with additionalEt₂₀ and dried to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamidehydrochloride (38 mg, 62% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.79 (s, 1H), 9.31 (s, 1H), 8.27 (br s, 1H), 8.23 (s, 1H), 7.59 (brs, 1H), 3.46-3.41 (m, 2H), 3.34-3.27 (m, 2H), 3.11-3.04 (m, 1H),2.88-2.80 (m, 1H), 2.17-2.11 (m, 1H), 1.94-1.85 (m, 3H), 1.79-1.74 (m,2H), 1.72-1.65 (m, 3H), 1.60-1.55 (m, 2H), 1.52-1.45 (m, 1H); LCMS(APCI+) m/z 406.0, 408.1 (M+H)+, Retention time=2.42 minutes (Method 2).

Example 31

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide

Step A: 2-Methoxyacetic acid (313 mg, 3.5 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (885 mg, 3.5 mmol) andtriethylamine (880 mg, 8.7 mmol) were added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (400 mg, 1.7 mmol,Example 1, Step H) in DCM (50 mL). The reaction was stirred at roomtemperature for 1 hour, and then 3M aqueous LiOH (4 mL) was added. Thereaction was stirred for 1 hour, and then saturated aqueous Na₂CO₃ wasadded (200 mL). The aqueous phase was extracted 3 times with DCM (200mL), and then the combined organic phases were dried over MgSO₄ andconcentrated to dryness.N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide(236 mg, 45% yield) was isolated as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide(100 mg, 0.3 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (199 mg,1.0 mmol) in n-BuOH (4 mL) were heated to 160° C. for 18 hours in asealed tube. After concentration, the residue was purified by C-18reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column,10-90% CH₃CN/water gradient; 30 CV) to yield (R)-tert-butyl1-(5-bromo-3-(2-methoxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(51 mg, 32% yield) as a solid.

Step C: (R)-tert-Butyl1-(5-bromo-3-(2-methoxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamatewas stirred in TFA (3 mL) for 30 minutes, and then the reaction wasconcentrated to dryness. The residue was purified by C-18 reverse phaseflash chromatography (Biotage SP4 unit, C-18 12M column, 0-50%CH₃CN/water gradient; 20 CV) to yield a solid. The solid was dissolvedin a minimal amount of methanol and was added dropwise to a 4N HCldioxane solution. The resulting solid was collected, rinsed with DCM anddried under high vacuum to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamidehydrochloride (22 mg, 55%) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ11.78 (d, 1H), 9.85 (s, 1H), 8.32 (br s, 3H), 8.27 (s, 1H), 7.93 (s,1H), 4.09 (q, 2H), 3.68-3.58 (m, 1H), 3.53-3.38 (m, 3H), 3.49 (s, 3H),3.32-3.26 (m, 1H), 3.02-2.96 (m, 1H), 2.24-2.18 (m, 1H), 1.92-1.82 (m,2H), 1.56-1.46 (m, 1H); LCMS (APCI+) m/z 365, 382 (M)+, Retentiontime=1.89 minutes (Method 1).

Example 32

(S—N-(4-((R)-3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide

Step A: (S)-2-Methoxypropanoic acid (181 mg, 1.74 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (443 mg, 1.74 mmol) andtriethylamine (440 mg, 4.35 mmol) were added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol,Example 1, Step H) in DCM (50 mL). The reaction was stirred at roomtemperature for 1 hour, and then 3M aqueous LiOH (4 mL) was added. Thereaction was stirred for 1 hour, and then saturated aqueous Na₂CO₃ wasadded (200 mL). The aqueous phase was extracted 3 times with DCM (200mL), and then the combined organic phases were dried over MgSO₄ andconcentrated to dryness. The residue was purified by C-18 reverse phaseflash chromatography (Biotage SP4 unit, C-18 25M column, 20-100%CH₃CN/water gradient; 20 CV) to yield(S)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide(131 mg, 48% yield) as a solid.

Step B:(S)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide(120 mg, 0.38 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (228 mg,1.14 mmol) in n-BuOH (4 mL) were heated to 160° C. for 18 hours in asealed tube. After concentration, the residue was purified by C-18reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column,10-90% CH₃CN/water gradient; 30 CV) to yield tert-butyl(R)-1-(5-bromo-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(84 mg, 45% yield) as a solid.

Step C: tert-Butyl(R)-1-(5-bromo-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(84 mg, 0.17 mmol) was stirred in TFA (3 mL) for 30 minutes, and thenthe reaction was concentrated to dryness. The residue was dissolved in aminimal amount of methanol, and then it was added dropwise to a 4N HCldioxane solution. The resulting solid was collected and rinsed with DCMand dried under high vacuum to yield(S)—N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamidehydrochloride (51 mg, 76% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.79 (d, 1H), 9.89 (s, 1H), 8.40 (br s, 3H), 8.27 (s, 1H), 7.96 (d,1H), 4.04 (q, 1H), 3.61-3.50 (m, 2H), 3.48-3.36 (m, 1H), 3.46 (s, 3H),3.34-3.28 (m, 1H), 3.02-2.96 (m, 1H), 2.26-2.18 (m, 1H), 1.92-1.82 (m,2H), 1.56-1.48 (m, 1H), 1.41 (d, 3H); LCMS (APCI+) m/z 379, 396 (M)+,Retention time=1.95 minutes (Method 1).

Example 33

N-(5-Bromo-4-(hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(100 mg, 0.3 mmol, Example 1, Step I) and tert-butylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (190 mg, 0.9 mmol) inn-BuOH (4 mL) were heated to 160° C. for 18 hours in a sealed tube.After concentration, the residue was purified by C-18 reverse phaseflash chromatography (Biotage SP4 unit, C-18 25M column, 10-90%CH₃CN/water gradient; 30 CV) to yield tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[2,3-c]pyrrole-5(1H)-carboxylateas a solid.

Step B: tert-Butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[2,3-c]pyrrole-5(1H)-carboxylate(84 mg, 0.16 mmol) was stirred in TFA (3 mL) for 30 minutes, and thenthe reaction was concentrated to dryness. The residue was dissolved in aminimal amount of methanol, and then it was added dropwise to a 4N HCldioxane solution. The resulting solid was collected, rinsed with DCM anddried under high vacuum to yieldN-(5-bromo-4-(hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (28mg, 41% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.15 (d, 1H),10.69 (s, 1H), 9.55 (br s, 1H), 9.47 (s, 1H), 9.39 (br s, 1H), 9.00 (d,1H), 8.94 (d, 1H), 8.31 (s, 1H), 7.99 (dd, 1H), 7.57 (d, 1H), 4.92-4.86(m, 1H), 3.74-3.67 (m, 1H), 3.27-3.19 (m, 2H), 3.14-3.07 (m, 1H),2.97-2.82 (m, 3H), 1.95-1.85 (m, 1H), 1.69-1.60 (m, 1H); LCMS (APCI+)m/z 427 (M)+, Retention time=1.99 minutes (Method 1).

Example 34

N-(4-(3-Amino-3-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide

Step A: Benzyl carbonochloridate (4.5 mL, 31.7 mmol) at 0° C. was addedto ethyl piperidine-3-carboxylate (5.0 g, 30.2 mmol) and K₂CO₃ (4.2 g,30.2 mmol) in 1:1 THF:water (100 mL). The reaction mixture was stirredat room temperature for 2 hours, and then ether (50 mL) was added. Theorganic layer was separated, washed with brine and dried over sodiumsulfate. After removal of the solvent, the residue was purified bychromatography on silica gel (hexane:ethyl acetate, 5:1) to give1-benzyl 3-ethyl piperidine-1,3-dicarboxylate (7.60 g 86% yield) as anoil.

Step B: Lithium bis(trimethylsilyl)amide (12.9 mL, 12.9 mmol, 1Msolution in THF) at −78° C. was added to 1-benzyl 3-ethylpiperidine-1,3-dicarboxylate (3.0 g, 10.3 mmol) in THF (20 mL), and thereaction was stirred at this temperature for 20 minutes. MeI (0.867 mL,13.9 mmol) was added, and the reaction was warmed to room temperature.After 2 hours at room temperature, the mixture was poured onto saturatedammonium chloride (20 mL) and extracted with ether, washed with brineand dried over sodium sulfate. After removal of the solvent, the residuewas purified by chromatography on silica gel (hexane:ethyl acetate, 5:1)to give 1-benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (3.1 g,98% yield) as an oil.

Step C: LiOH (15.0 mL, 30.1 mmol) was added to 1-benzyl 3-ethyl3-methylpiperidine-1,3-dicarboxylate (3.0 g, 10.0 mmol) in ethanol (15mL), and the reaction mixture was stirred at 86° C. for 1 hour. Theethanol was removed, and ether (30 mL) was added. The aqueous layer wasseparated and acidified with saturated potassium hydrogen sulfate to apH of about 3 to about 4, extracted with ethyl acetate (50 mL), washedwith brine and dried over sodium sulfate. After removal of the solvent,1-(benzyloxycarbonyl)-3-methylpiperidine-3-carboxylic acid (2.6 g, 92%yield) was isolated as an oil.

Step D: Diphenylphosphoryl azide (“DPPA”; 2.4 mL, 11.1 mmol) was addedto 1-(benzyloxycarbonyl)-3-methylpiperidine-3-carboxylic acid (2.5 g,9.2 mmol) and TEA (1.5 mL, 11.1 mmol) in t-BuOH (17.7 mL, 184.6 mmol).The mixture was heated at reflux for 6 hours and then was transferred toa sealed tube and heated at 126° C. for 3 days. The solvent was removed,and then ether (50 mL) and saturated sodium bicarbonate (30 mL) wereadded. The organic layer was separated, washed with brine, dried oversodium sulfate. After removal of the solvent, the residue was purifiedby chromatography on silica gel (hexane:ethyl acetate, 5:1) to givebenzyl 3-(tert-butoxycarbonylamino)-3-methylpiperidine-1-carboxylate(1.4 g, 43% yield) as a solid.

Step E: Benzyl3-(tert-butoxycarbonylamino)-3-methylpiperidine-1-carboxylate (1.4 g,4.0 mmol) and 10% Pd/C (0.21 g, 0.2 mmol) in MeOH (20 mL) were stirredunder an H₂ atmosphere (1 atm) for 1 hour. The catalyst was removed byfiltration and washed with methanol. The filtrate was concentrated togive tert-butyl 3-methylpiperidin-3-ylcarbamate (0.62 g, 72% yield) as asolid.

Step F:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide(100 mg, 0.331 mmol, Example 31, Step A) and tert-butyl3-methylpiperidin-3-ylcarbamate (213 mg, 0.993 mmol) in n-BuOH (4 mL)were heated to 160° C. for 48 hours in a sealed tube. Afterconcentration, the residue was purified by C-18 reverse phase flashchromatography (Biotage SP4 unit, C-18 25M column, 10-90% CH₃CN/watergradient; 30 CV) to yieldN-(4-(3-amino-3-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide(65 mg, 49% yield) as a solid and tert-butyl1-(5-bromo-3-(2-methoxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)-3-methylpiperidin-3-ylcarbamate(32 mg, 19% yield) as an oil.

Step G:N-(4-(3-Amino-3-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide(65 mg, 0.16 mmol) was dissolved in a minimal amount of methanol andthen added to a stirred solution of 4N HCl in dioxane. The resultingsolid was filtered and dried under high vacuum to yieldN-(4-(3-amino-3-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamidehydrochloride (36 mg, 55% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.90 (d, 1H), 9.38 (s, 1H), 8.26 (s, 1H), 8.24 (br s, 2H), 6.30 (brs, 3H), 4.11 (q, 2H), 3.43 (s, 3H), 3.30-3.21 (m, 1H), 3.20-3.05 (m,3H), 2.00-1.90 (m, 1H), 1.86-1.75 (m, 3H), 1.46 (s, 3H); LCMS (APCI+)m/z 379, 396 (M)+, Retention time=1.90 minutes (Method 1).

Example 35

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methoxypicolinamide

Step A: A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H) in CH₂Cl₂ (10 mL) was treatedwith 6-methoxypicolinic acid (160 mg, 1.04 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (332 mg, 1.30 mmol) andtriethylamine (440 mg, 4.35 mmol). The reaction was stirred at roomtemperature for 1 hour, and then 2M aqueous LiOH (3 mL) was added. Thereaction was stirred for 1 hour, and then water was added (10 mL). Thesolid, which separated, was filtered and washed with CH₂Cl₂ (10 mL). Thefiltered cake was dried to yieldN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methoxypicolinamide(229 mg, 72% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.17 (s, 1H), 12.25(s, 1H), 8.40 (d, 1H), 7 96 (dd, 1H), 7.92 (dd. 1H), 7.74 (dd. 1H), 7.11(dd, 1H), 4.05 (s, 3H); LCMS (APCI+) m/z 365, 366.9 (M+H)+, Retentiontime=3.75 minutes (Method 2).

Step B: A solution ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-methoxypicolinamide(228 mg, 0.624 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butylpiperidin-3-ylcarbamate (375 mg, 1.87 mmol) and stirred at 160° C. for48 hours in a sealed tube. The mixture was concentrated in vacuo, andthe residue diluted with water (25 mL) and extracted with EtOAc (3×20mL). The combined organic extracts were dried over anhydrous magnesiumsulfate and filtered. The filtrate was concentrated in vacuo andpurified by C-18 reverse phase flash chromatography (Biotage SP4 unit,C-18 25M column, 5-85% CH₃CN/water gradient; 25 CV) to provide(R)-tert-butyl1-(5-bromo-3-(6-methoxypicolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(91.5 mg, 27% yield) as a solid. LCMS (APCI+) m/z 445.1, 447.1, 454.1(M+H)+, Retention time=4.03 minutes (Method 2).

Step C: (R)-tert-Butyl1-(5-bromo-3-(6-methoxypicolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(90 mg, 0.17 mmol) in TFA (3 mL) was stirred at room temperature for 45minutes and then concentrated in vacuo. The residue was dissolved inminimal methanol, and 2N HCl in ether was added. The precipitate formedwas filtered and dried under high vacuum to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)6-methoxypicolinamidehydrochloride (27 mg, 29% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.86 (s,1H), 10.84 (br s, 1H), 8.34 (br s, 2H), 8.29 (s, 1H), 8.80 (d, 2H), 7.81(d, 1H), 7.26 (d, 1H), 4.04 (s, 3H), 3.96-3.84 (m, 1H), 3.74-3.64 (m,1H), 3.56-3.46 (m, 1H), 3.40-3.24 (m, 1H), 3.08-3.00 (m, 1H), 2.28-2.12(m, 2H), 1.84-1.74 (m, 1H), 1.56-1.44 (m, 1H); LCMS (APCI+) m/z 428,445, 447.0 (M+H)+, Retention time=2.61 minutes (Method 2).

Example 36

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2-carboxamide

Step A: A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H) in CH₂Cl₂ (10 mL) was treatedwith pyrimidine-2-carboxylic acid (129 mg, 1.04 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (332 mg, 1.30 mmol) andtriethylamine (440 mg, 4.35 mmol). The reaction was stirred at roomtemperature for 48 hour, and then water (10 mL) was added. The reactionwas stirred for 1 hour. The solid which separated was filtered andwashed with CH₂Cl₂ (10 mL). The filtered cake was dried to yieldN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2-carboxamide(110 mg, 38% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.21 (br s, 1H),10.47 (s, 1H), 9.06 (d, 2H), 8.40 (d, 1H), 7 87 (d, 1H), 7.77 (t, 1H);LCMS (APCI+) m/z 335.9, 337.9 (M+H)+, Retention time=2.70 minutes(Method 2).

Step B: A solution ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2-carboxamide(110 mg, 0.328 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butylpiperidin-3-ylcarbamate (197 mg, 0.982 mmol) and stirred at 160° C. for48 hours in a sealed tube. The mixture was concentrated in vacuo, andthe residue was diluted with water (25 mL) and extracted with EtOAc(3×20 mL). The combined organic extracts were dried over anhydrousmagnesium sulfate and filtered. The filtrate was concentrated in vacuo,and the residue purified by C-18 reverse phase flash chromatography(Biotage SP4 unit, C-18 25M column, 5-85% CH₃CN/water gradient; 25 CV)to provide (R)-tert-butyl1-(5-bromo-3-(pyrimidine-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(67.6 mg, 40% yield) as a solid. LCMS (APCI+) m/z 416, 418 (M+H)+,Retention time=3.40 minutes (Method 2).

Step C: (R)-tert-Butyl1-(5-bromo-3-(pyrimidine-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(67 mg, 0.13 mmol) in TFA (3 mL) was stirred at room temperature for 45minutes and concentrated in vacuo. The residue was dissolved in minimalmethanol, and 2N HCl in ether was added. The precipitate formed wasfiltered and dried under high vacuum to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-2-carboxamidehydrochloride salt (10 mg, 16% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ11.87 (s, 1H), 11.38 (br s, 1H), 9.14 (d, 2H), 8.32 (s, 1H), 8.23 (s,3H), 8.18-8.16 (m, 1H), 7.87-7.81 (m, 1H), 3.96-3.84 (m, 1H), 3.74-3.64(m, 1H), 3.60-3.50 (m, 1H), 3.40-3.32 (m, 1H), 3.08-3.00 (m, 1H),2.42-2.32 (m, 1H), 2.18-2.04 (m, 1H), 1.62-1.48 (m, 1H); LCMS (APCI+)m/z 399, 416.0 (M+H)+, Retention time=2.25 minutes (Method 2).

Example 37

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpicolinamide

Step A: A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H) in CH₂Cl₂ (10 mL) was treatedwith 3-methylpicolinic acid (143 mg, 1.04 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (332 mg, 1.30 mmol) andtriethylamine (440 mg, 4.35 mmol). The reaction was stirred at roomtemperature for 1 hour. The mixture was filtered to remove the product,and the filtrate was concentrated in vacuo. The residue was stirred inanhydrous THF (10 mL), treated with 2M LiOH solution (3 mL) and stirredat room temperature for 1 hour. The organic solvent was removed invacuo, and then water (10 mL) was added. The reaction stirred for 1hour. The solid, which separated, was filtered and washed with water andCH₂Cl₂ (10 mL). The combined filtered cakes were dried to yieldN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpicolinamide(197 mg, 65% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.13 (br s, 1H),10.42 (s, 1H), 8.56 (d, 1H), 8.39 (d, 1H), 7 87 (d, 1H), 7 84 (d, 1H),7.55 (dd, 1H) 2.67 (s, 3H); LCMS (APCI+) m/z 349.1, 351 (M+H)+,Retention time=3.42 minutes (Method 3).

Step B: A solution ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpicolinamide(197 mg, 0.566 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butylpiperidin-3-ylcarbamate (453 mg, 2.263 mmol) and stirred at 160° C. for48 hours in a sealed tube. The mixture was concentrated in vacuo, andthe residue diluted with water (25 mL) and extracted with EtOAc (3×20mL). The combined organic extracts were dried over anhydrous magnesiumsulfate and filtered. The filtrate concentrated in vacuo, and theresidue was purified by C-18 reverse phase flash chromatography (BiotageSP4 unit, C-18 25M column, 5-85% CH₃CN/water gradient; 25 CV) to provide(R)-tert-butyl1-(5-bromo-3-(3-methylpicolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(83.8 mg, 28% yield) as a solid. LCMS (APCI+) m/z 429.1, 431.1, 531.1(M+H)+, Retention time=4.32 minutes (Method 2).

Step C: (R)-tert-Butyl1-(5-bromo-3-(3-methylpicolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(83 mg, 0.16 mmol) in TFA (5 mL) was stirred at room temperature for 1.5hours and concentrated in vacuo. The residue was purified by C-18reverse phase flash chromatography (Biotage SP4 unit, C-18 12M column,3-65% CH₃CN/water gradient; 14 CV). The residue was dissolved in minimalmethanol, and 2N HCl in ether was added. The precipitate formed wasfiltered and dried under high vacuum to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylpicolinamidehydrochloride (65.9 mg, 78% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.85(s, 1H), 11.38 (br s, 1H), 8.69 (d, 1H), 8.38 (br s, 21H), 8.30 (s, 1H),8.16 (d, 1H), 7.89 (d, 1H), 7.66-7.60 (m, 1H), 3.98-3.84 (m, 1H),3.78-3.68 (m, 1H), 3.60-3.48 (m, 1H), 3.40-3.32 (m, 1H), 3.08-2.80 (m,1H), 2.76 (s, 3H), 2.42-2.32 (m, 1H), 2.14-2.00 (m, 1H), 1.90-1.78 (m,1H) 1.64-1.48 (m, 1H); LCMS (APCI+) m/z 412, 429 (M+H)+, Retentiontime=2.66 minutes (Method 2).

Example 38

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(trifluoromethyl)cyclopropanecarboxamide

Step A: A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H) in CH₂Cl₂ (10 mL) was treatedwith (trifluoromethyl)cyclopropanecarboxylic acid (161 mg, 1.04 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (332 mg, 1.30 mmol) andtriethylamine (440 mg, 4.35 mmol). The reaction was stirred at roomtemperature for 1 hour. The mixture was concentrated in vacuo. Theresidue was stirred in anhydrous THF (10 mL), treated with 2M LiOHsolution (3 mL) and stirred at room temperature for 1 hour. The organicsolvent was removed in vacuo, and then water (10 mL) was added. Thereaction was stirred for 1 hour. The solid, which separated, wasfiltered and washed with water and CH₂Cl₂ (10 mL). The filtered cake wasdried to yieldN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(trifluoromethyl)cyclopropanecarboxamide(229.5 mg, 72% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.15 (br s, 1H),9.38 (s, 1H), 8.36 (d, 1H), 7.51 (s, 1H), 1.49-1.43 (m, 2H), 1.38-1.33(m, 2H); LCMS (APCI+) m/z 366, 368 (M+H)+, Retention time=3.32 minutes(Method 3).

Step B: A solution ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(trifluoromethyl)cyclopropanecarboxamide(229 mg, 0.627 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butylpiperidin-3-ylcarbamate (505 mg, 2.507 mmol) and stirred at 160° C. for48 hours in a sealed tube. The mixture was concentrated in vacuo, andthe residue diluted with water (25 mL) and extracted with EtOAc (3×20mL). The combined organic extracts were dried over anhydrous magnesiumsulfate and filtered. The filtrate was concentrated in vacuo. Theresidue was purified by C-18 reverse phase flash chromatography (BiotageSP4 unit, C-18 25M column, 5-85% CH₃CN/water gradient; 25 CV) to provide(R)-tert-butyl1-(5-bromo-3-(1-(trifluoromethyl)cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(65 mg, 19% yield) as a solid. LCMS (APCI+) m/z 429.1, 446.1, 492.1,548.1 (M+H)+, Retention time=3.79 minutes (Method 3).

Step C: (R)-tert-Butyl1-(5-bromo-3-(1-(trifluoromethyl)cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(65 mg, 0.12 mmol) in TFA (5 mL) was stirred at room temperature for 1.5hours and concentrated in vacuo. The residue was purified by C-18reverse phase flash chromatography (Biotage SP4 unit, C-18 12M column,3-65% CH₃CN/water gradient; 14 CV). The residue obtained was dissolvedin minimal methanol, and 2N HCl in ether was added. The precipitateformed was filtered and dried under high vacuum to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(trifluoromethyl)cyclopropanecarboxamidehydrochloride (58 mg, 94% yield). ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.97 (brs, 1H), 9.32 (s, 1H), 8.39 (s, 2H), 8.27 (s, 1H), 7.63 (s, 1H),3.50-3.22 (m, 4H), 3.15-3.04 (m, 1H), 2.20-2.10 (m, 1H), 1.90-1.78 (m,1H), 1.76-1.46 (m, 4H), 1.36-1.44 (m, 2H); LCMS (APCI+) m/z 429.2,446.1, 448.0 (M+H)+, Retention time=2.07 minutes (Method 3).

Example 39

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxybenzamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (250 mg, 1.09mmol, Example 1, Step H), 3-methoxybenzoyl chloride (389 mg, 2.28 mmol),and triethylamine (757 μL, 5.43 mmol) were placed in DCM (5 mL) andstirred at room temperature for 30 minutes. 3M LiOH (3 mL) was added.The reaction was stirred for 10 minutes and then poured onto water. Themixture was then filtered and washed with DCM and water to provide solidN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxybenzamide(219 mg, 55% yield).

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxybenzamide(215 mg, 0.590 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (414 mg,2.07 mmol) were placed in n-BuOH (5 mL) and heated to 155° C. for 72hours. The reaction was then cooled to room temperature and concentratedto dryness. The crude residue was purified by C-18 reverse phase flashchromatography (Biotage Horizon unit, C-18 25M column, 5-90% CH₃CN/watergradient) to give (R)-tert-butyl1-(5-bromo-3-(3-methoxybenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(238 mg, 74% yield).

Step C: (R)-tert-Butyl1-(5-bromo-3-(3-methoxybenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(238 mg, 0.437 mmol) in TFA (2 mL) was stirred for 20 minutes at roomtemperature and was then concentrated. The residue was purified by C-18reverse phase flash chromatography (Biotage Horizon unit, C-18 25Mcolumn, 0-50% CH₃CN/water with 0.1% TFA) to provide the TFA salt, whichwas redissolved in 10% MeOH in DCM (2 mL) and added dropwise to astirred solution of 2M HCl in ether. The resulting precipitate wasfiltered and dried to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxybenzamidehydrochloride (96 mg, 42% yield). ¹H NMR (400 MHz, D₂O) δ 8.20 (s, 1H),7.41 (d, 2H), 7.39 (s, 1H), 7.34 (s, 1H), 7.15 (m, 1H), 3.75 (s, 3H),3.48 (d, 1H), 3.30-3.05 (m, 4H), 1.78 (m, 1H), 1.62 (m, 1H), 1.46-1.28(m, 2H); LCMS (APCI+) m/z 447.1 (M+H)+, Retention time=2.36 minutes(Method 2).

Example 40

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylnicotinamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869mmol, Example 1, Step H), 2-methylnicotinic acid (250 mg, 1.83 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (465 mg, 1.83 mmol), andtriethylamine (0.606 mL, 4.35 mmol) were placed in DCM (5 mL) andstirred at room temperature for 90 minutes. 3M LiOH (5 mL) was added.The reaction was stirred for 20 minutes and then was poured onto water.The mixture was then filtered and washed with water and DCM. Thefiltered solid was dried to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylnicotinamide(254 mg, 84% yield).

Step B: (R)-tert-Butyl1-(5-bromo-3-(2-methylnicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(190 mg, 49.3% yield) was prepared according to Example 39, Step B, fromN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylnicotinamide(254 mg, 0.727 mmol). The reaction was heated for 48 hours instead of 72hours.

Step C: 4N HCl in dioxane (3 mL) was added to (R)-tert-butyl1-(5-bromo-3-(2-methylnicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(190 mg, 0.359 mmol) in DCM (3 mL), and the reaction stirred at roomtemperature for 30 minutes. After concentration, the residue waspurified by C-18 reverse phase flash chromatography (Biotage Horizonunit, C-18 25M column, 5-90% CH₃CN/water gradient). The compound waspurified again by C-18 reverse phase flash chromatography (BiotageHorizon unit, C-18 25M column, 5-80% CH₃CN/water gradient). The compoundwas then purified again by C-18 reverse phase flash chromatography(Biotage Horizon unit, C-18 25M column, 0-50% CH₃CN/water with 0.1% TFA)to provide the TFA salt, which was redissolved in 10% MeOH in DCM andadded dropwise to a stirred 2N HCl in ether solution. The resultingprecipitate was filtered and dried to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylnicotinamidehydrochloride (52.1 mg, 26% yield). ¹H NMR (400 MHz, D₂O) δ 8.66 (dd,1H), 8.60 (dd, 1H), 8.24 (s, 1H), 7.86 (m, 1H), 7.25 (s, 1H), 3.59 (d,1H), 3.41 (m, 1H), 3.30-3.15 (m, 3H), 2.76 (s, 3H), 1.92 (m, 1H), 1.77(m, 1H), 1.47 (m, 2H); LCMS (APCI+) m/z 431.1 (M+H)+, Retentiontime=2.18 minutes (Method 2).

Example 41

(R)—N-(4-(3-Aminopiperidin-1-yl-5-brom-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluorobenzamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869mmol, Example 1, Step H), 3-fluorobenzoic acid (256 mg, 1.83 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (465 mg, 1.83 mmol), andtriethylamine (0.606 mL, 4.35 mmol) were placed in DCM (5 mL) andstirred at room temperature for 30 minutes. 3M LiOH (3 mL) was thenadded. The reaction was stirred for 10 minutes and then poured intowater. The aqueous layer was extracted several times with DCM, and thecombined organic phases were dried, filtered, and concentrated to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluorobenzamide.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluorobenzamide(306 mg, 0.869 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (522 mg,2.61 mmol) were placed in n-BuOH (5 mL) and heated to 155° C. for 42hours in a sealed tube. The reaction was cooled to room temperature andconcentrated to dryness. The crude residue was purified by C-18 reversephase flash chromatography (Biotage Horizon unit, C-18 25M column, 5-80%CH₃CN/water gradient) to give (R)-tert-butyl1-(5-bromo-3-(3-fluorobenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(125 mg, 27% yield).

Step C:(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluorobenzamidehydrochloride (41.2 mg, 35% yield) was prepared according Example 39,Step C, from (R)-tert-butyl1-(5-bromo-3-(3-fluorobenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(125 mg, 0.235 mmol). ¹H NMR (400 MHz, D₂O) δ 8.27 (s, 1H), 7.65 (d,1H), 7.56 (d, 1H), 7.49 (m, 1H), 7.39 (s, 1H), 7.31 (t, 1H), 3.70 (d,1H), 3.41 (m, 1H), 3.32 (d, 1H), 3.21-3.07 (m, 2H), 1.86 (m, 1H), 1.64(m, 1H), 1.51 (m, 1H), 1.35 (m, 1H); LCMS (APCI+) m/z 432.0 (M+H)+,Retention time=2.34 minutes (Method 2).

Example 42

(R)—N-(4-(3-Aminopiperidin-1-yl-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-chloropicolinamide

Step A: TEA (0.61 mL, 4.35 mmol) was added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol,Example 1, Step H), 5-chloropicolinic acid (160 mg, 1.04 mmol) andBOP-Cl (332 mg, 1.30 mmol) in DCM (5 mL). The reaction was stirred atroom temperature for 1 hour, and then a LiOH solution (2 N, 3 mL) wasadded. The mixture was stirred for 30 minutes, and water (10 mL) wasadded. The solid formed was collected by filtration, washed with DCM (10mL) and dried to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-chloropicolinamide(240 mg, 73% yield) as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-chloropicolinamide(240 mg, 0.64 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (380 mg,1.91 mmol) and DIEA (0.17 mL, 0.95 mmol) in n-BuOH (2 mL) were stirredat 148° C. (bath) for 40 hours. The solvent was removed, and the residuewas dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine(10 mL) and dried over sodium sulfate. After removal of the solvent, theresidue was purified by C-18 reverse phase flash chromatography (BiotageSP4 unit, C-18 25M column, 30-75% CH₃CN/water gradient; 30 CV) to give asolid. This solid was dissolved in DCM (3 mL) and TFA (0.5 mL) wasadded. The mixture was stirred at room temperature for 1 hour. Thesolvent was removed. The residue was dissolved in DCM (1 mL), and 2N HClin ether (3 mL) was added. The solid formed was collected by filtrationto give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-chloropicolinamidehydrochloride (50 mg, 14% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.24 (s, 1H), 8.08 (s, 1H), 7.63 (m, 1H), 7.55-7.58 (m, 2H), 3.59 (m,1H), 3.42 (m, 1H), 3.35 (m, 1H), 3.27 (m, 1H), 2.77 (m, 1H), 2.11 (m,1H), 1.87 (m, 1H), 1.68 (m, 1H), 1.40-1.48 (m, 1H); LCMS (APCI+) m/z 451(M+H)+.

Example 43

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)picolinamide

Step A: TEA (0.61 mL, 4.35 mmol) was added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol,Example 1, Step H), 5-(trifluoromethyl)picolinic acid (200 mg, 1.04mmol) and BOP-Cl (330 mg, 1.30 mmol) in DCM (5 mL). The reaction wasstirred at room temperature for 1 hour, and then a LiOH solution (3 mL,2N) was added. The mixture was stirred for 30 minutes, and water (10 mL)was added. The solid formed was collected by filtration, washed with DCM(10 mL) and dried to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)picolinamide(195 mg, 55% yield) as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)picolinamide (195 mg, 0.48 mmol), (R)-tert-butyl piperidin-3-ylcarbamate(290 mg, 1.45 mmol) and DIEA (0.17 mL, 0.97 mmol) in N-methylpyrrolidone(“NMP”; 2 mL) were stirred at 148° C. (bath) for 18 hours and at 160° C.for 5 hours. Ethyl acetate (20 mL) was added, and the mixture was washedwith water (10 mL), brine (10 mL) and dried over sodium sulfate. Afterremoval of the solvent, the residue was purified by C-18 reverse phaseflash chromatography (Biotage SP4 unit, C-18 25M column, 45-85%CH₃CN/water gradient; 30 CV) to give a solid. This solid was dissolvedin DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred atroom temperature for 1 hour. The solvent was removed. The residue wasdissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solidformed was collected by filtration to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)picolinamide (24 mg, 8% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ 8.77(s, 1H), 8.15 (s, 1H), 8.11 (d, 1H), 7.95 (d, 1H), 7.82 (s, 1H), 3.74(m, 1H), 3.59 (m, 1H), 3.48 (m, 1H), 3.32 (m, 1H), 2.88 (m, 11H), 2.22(m, 1H), 2.03 (m, 1H), 1.79 (m, 1H), 1.53 (m, 1H); LCMS (APCI+) m/z 483(M+H)+.

Example 44

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide

Step A: Picolinoyl chloride hydrochloride (270 mg, 1.53 mmol) was addedto 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (240mg, 1.02 mmol, Example 11, step G) in pyridine (5 mL). The reaction wasstirred at 0° C. for 10 minutes, and then the pyridine was removed. THF(5 mL) and 2N LiOH (3 mL) were added and stirred for 20 minutes. The THFwas removed, and water (20 mL) was added. The solid formed was collectedby filtration and dried to giveN-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide(280 mg, 79% yield) as a solid.

Step B:N-(4-Chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide(280 mg, 0.81 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (490 mg,2.42 mmol) and DIEA (0.28 mL, 1.61 mmol) in NMP (2 mL) were stirred at156° C. (bath) for 10 hours. Ethyl acetate (20 mL) was added, theorganic layer was washed with water (10 mL), brine (10 mL) and driedover sodium sulfate. After removal of the solvent, the residue waspurified by C-18 reverse phase flash chromatography (Biotage SP4 unit,C-18 25M column, 40-80% CH₃CN/water gradient; 30 CV) to give a solid.This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. Themixture was stirred at room temperature for 1 hour. The solvent wasremoved. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3mL) was added. The solid formed was collected by filtration to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamidehydrochloride (195 mg, 47% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.40 (m, 1H), 8.37 (s, 1H), 7.86 (s, 1H), 7.81 (m, 2H), 7.44 (m, 1H),3.68 (m, 1H), 3.36 (m, 1H), 2.99 (m, 1H), 2.93 (m, 1), 2.53 (m, 1H),2.05 (m, 1H), 1.87 (m, 1H), 1.66 (m, 1H), 1.42 (m, 1H); LCMS (APCI+) m/z405 (M+H)+.

Example 45

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide

Step A: TEA (1.21 mL, 8.69 mmol) was added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (400 mg, 1.74 mmol,Example 1, Step H), 1-methyl-1H-pyrazole-3-carboxylic acid (260 mg, 2.09mmol) and BOP-Cl (60 mg, 2.61 mmol) in DCM (5 mL). The reaction wasstirred at room temperature for 1 hour, and then a LiOH solution (3 mL,2N) was added. The mixture was stirred for 30 minutes, and water (10 mL)was added. The solid formed was collected by filtration, washed with DCM(5 mL) and dried to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide(30 mg, 66% yield) as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxamide(0.190 g, 0.56 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (0.34 g,1.69 mmol) and DIEA (0.2 mL, 1.12 mmol) in NMP (2 mL) were stirred at156° C. (bath) for 24 hours. The solvent was removed, and the residuedissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10mL) and dried over sodium sulfate. After removal of the solvent, theresidue was purified by C-18 reverse phase flash chromatography (BiotageSP4 unit, C-18 25M column, 30-70% CH₃CN/water gradient; 30 CV) to give asolid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) wasadded. The mixture was stirred at room temperature for 1 hour. Thesolvent was removed. The residue was dissolved in DCM (1 mL), and 2N HClin ether (3 mL) was added. The solid formed was collected by filtrationto give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H-pyrazole-3-carboxamidehydrochloride (0.0096 g, 3% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.22 (s, 1H), 7.73 (s, 1H), 7.60 (d, 1H), 6.70 (d, 1H), 3.86 (s, 3H),3.70 (m, 1H), 3.52 (m, 1H), 3.40 (m, 2H), 2.98 (m, 1H), 2.12 (m, 1H),1.94 (m, 1H), 1.76 (m, 1H), 1.48-1.54 (m, 1H); LCMS (APCI+) m/z 418(M+H)+.

Example 46

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide

Step A: TEA (0.61 mL, 4.35 mmol) was added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.20 g, 0.87 mmol,Example 1, Step H), 1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylicacid (0.16 g, 1.04 mmol) and BOP-Cl (0.29 g, 1.13 mmol) in DCM (5 mL).The reaction was stirred at room temperature for 1 hour, and then a LiOHsolution (3 mL, 2N) was added. The mixture was stirred for 30 minutes,and water (10 mL) was added. The solid formed was collected byfiltration, washed with DCM (5 mL) and dried to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide(0.223 g, 70% yield) as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide(0.223 g, 0.61 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (0.366 g,1.83 mmol) and DIEA (0.21 mL, 1.22 mmol) in NMP (2 mL) were stirred at156° C. (bath) for 18 hours. The solvent was removed, and the residuewas dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine(10 mL) and dried over sodium sulfate. After removal of the solvent, theresidue was purified by C-18 reverse phase flash chromatography (BiotageSP4 unit, C-18 25M column, 30-70% CH₃CN/water gradient; 30 CV) to give asolid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) wasadded. The mixture was stirred at room temperature for 1 hour. Thesolvent was removed. The residue was dissolved in DCM (1 mL), and 2N HClin ether (3 mL) was added. The solid formed was collected by filtrationto give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamidehydrochloride (0.022 g, 6% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.20 (s, 1H), 7.87 (d, 1H), 7.56 (s, 1H). 7.01 (d, 1H), 3.74 (s, 3H),3.54 (m, 1H), 3.41 (m, 1H), 3.36 (m, 2H), 3.15 (m, 1H), 2.01 (m, 1H),1.75 (m, 1H), 1.67 (m, 1H), 1.41-1.49 (m, 1H); LCMS (APCI+) m/z 446(M+H)+.

Example 47

N-(4-(3-Amino-3-methylpyrrolidin-1-yl-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: Benzyl carbonochloridate (3.57 mL, 25.36 mmol) at 0° C. wasadded to methyl pyrrolidine-3-carboxylate hydrochloride (4.00 g, 24.15mmol) and K₂CO₃ (6.68 g, 48.3 mmol) in THF:water (100 mL, 1:1). Thereaction mixture was stirred at room temperature for 2 hours. Ether (50mL) was added. The organic layer was separated, washed with brine anddried over sodium sulfate. After removal of the solvent, the residue waspurified by chromatography (hexane:ethyl acetate, 3:1) to give 1-benzyl3-methyl pyrrolidine-1,3-dicarboxylate (3.45 g, 54% yield) as an oil.

Step B: Lithium bis(trimethylsilyl)amide (16.4 mL, 16.4 mmol) was addedto 1-benzyl 3-methyl pyrrolidine-1,3-dicarboxylate (3.45 g, 13.1 mmol)in THF (20 mL) at −78° C., and the reaction was stirred at −78° C. for20 minutes. MeI (1.10 mL, 17.7 mmol) was added, and the reaction waswarmed to room temperature. After 2 hours at room temperature, themixture was poured onto saturated ammonium chloride (20 mL), extractedwith ether, washed with brine and dried over sodium sulfate. Afterremoval of the solvent, the residue was purified by chromatography(hexane:ethyl acetate, 4:1) to give 1-benzyl 3-methyl3-methylpyrrolidine-1,3-dicarboxylate (2.72 g, 75% yield) as an oil.

Step C: 1-Benzyl 3-methyl 3-methylpyrrolidine-1,3-dicarboxylate (2.72 g,9.81 mmol) in ethanol (15 mL) was added to a 3M LiOH solution (14.7 mL,29.4 mmol), and the reaction mixture was stirred at 78° C. (bath) for 1hour. The ethanol was removed and, ether (30 mL) was added. The aqueouslayer was separated and acidified with saturated potassium hydrogensulfate to a pH of about 3 to about 4, extracted with ethyl acetate (50mL), washed with brine and dried over sodium sulfate. After removal ofthe solvent, 1-(benzyloxycarbonyl)-3-methylpyrrolidine-3-carboxylic acid(2.56 g, 99% yield) was isolated as an oil.

Step D: DPPA (2.52 mL, 11.67 mmol) was added to1-(benzyloxycarbonyl)-3-methylpyrrolidine-3-carboxylic acid (2.56 g,9.72 mmol) and TEA (1.63 mL, 11.7 mmol) in t-BuOH (27.9 mL, 291.7 mmol).The mixture was heated at reflux for 1 hour, and then was transferred toa sealed tube and heated at 100° C. (bath) for 24 hours. The solvent wasremoved, and ether (50 mL) and saturated sodium bicarbonate (30 mL) wereadded. The organic layer was separated, washed with brine and dried oversodium sulfate. After removal of the solvent, the residue was purifiedby chromatography (hexane:ethyl acetate, 5:1) to give benzyl3-(tert-butoxycarbonylamino)-3-methylpyrrolidine-1-carboxylate (2.0 g,61% yield) as an oil.

Step E: Benzyl3-(tert-butoxycarbonylamino)-3-methylpyrrolidine-1-carboxylate (2.00 g,5.98 mmol) and 10% Pd/C (0.32 g, 0.30 mmol) in MeOH (20 mL) were stirredunder 1 atmosphere of H₂ for 1 hour. The catalyst was removed byfiltration and washed with methanol. The filtrate was concentrated togive tert-butyl 3-methylpyrrolidin-3-ylcarbamate (1.15 g, 96%) as asolid.

Step F: N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(0.085 g, 0.254 mmol, Example 1, Step I), tert-butyl3-methylpyrrolidin-3-ylcarbamate (0.152 g, 0.76 mmol) and DIEA (0.08 mL,0.5 mmol) in n-BuOH (2 mL) were stirred at 156° C. (bath) for 6 hours.The solvent was removed, and the residue dissolved in ethyl acetate (20mL), washed with water (10 mL), brine (10 mL) and dried over sodiumsulfate. After removal of the solvent, the residue was purified by C-18reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column,10-80% CH₃CN/water gradient; 25 CV) to give a solid. This solid wasdissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture wasstirred at room temperature for 1 hour. The solvent was removed. Theresidue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) wasadded. The solid formed was collected by filtration to giveN-(4-(3-amino-3-methylpyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (0.072 g, 54% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ9.16 (s, 1H), 8.84 (d, 1H), 8.78 (d, 1H), 8.22 (s, 1H), 7.98 (m, 1H),7.40 (s, 1H), 3.80-3.94 (m, 3H), 3.62 (m, 1H), 2.04 (m, 1H), 1.85 (m,1H), 1.23 (s, 3H); LCMS (APCI+) m/z 415 (M+H)+.

Example 48

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)quinoxaline-2-carboxamide

Step A: 4-Chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine(0.200 g, 0.849 mmol, Example 11, Step G) and pyrazine-2-carboxylic acid(0.221 g, 1.78 mmol) were placed in DCM (5 mL) at room temperature.BOP-Cl (0.454 g, 1.78 mmol) was then added, followed by the addition oftriethylamine (0.592 mL, 4.24 mmol). The reaction was stirred for 1hour. 3M aqueous LiOH (3 mL) was then added, and the reaction wasstirred for 10 minutes. Water (10 mL) and DCM (10 mL) were then added,and the reaction was filtered. The resulting solid was slurried with10:1 DCM:MeOH and filtered to give solidN-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide(0.23 g, 79% yield).

Step B:N-(4-Chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamide(0.230 g, 0.673 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.404g, 2.02 mmol) were placed in n-BuOH (3 mL) and heated to 155° C. for 18hours in a sealed tube. The reaction was then cooled to room temperatureand concentrated to dryness. The resulting residue was purified by C-18reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column,5-75% CH₃CN/water gradient; 25 CV) to give (R)-tert-butyl1-(3-(pyrazine-2-carboxamido)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.120 g, 35% yield).

Step C: (R)-tert-Butyl1-(3-(pyrazine-2-carboxamido)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.120 g, 0.237 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added, and the reaction was stirred at room temperaturefor 1 hour. The reaction was then concentrated to dryness to give thecrude product, which was purified C-18 reverse phase flashchromatography (Biotage SP4 unit, C-18 25M column, 0-50% CH₃CN/watergradient; 25 CV). The purified product was then dissolved in DCM (withminimal MeOH to aid solubility) and added dropwise to a stirringsolution of 1M HCl in ether. The resulting solid was filtered, dried andcollected to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazine-2-carboxamidehydrochloride (0.071 g, 62% yield). ¹H NMR (400 MHz, D₂O) δ 8.84 (s,1H), 8.59-8.59 (m, 1H), 8.52-8.52 (m, 1H), 8.31 (s, 1H), 7.79 (s, 1H),3.62-3.54 (m, 1H), 3.37-3.33 (m, 1H), 3.00-2.92 (m, 3H), 2.04-2.01 (m,1H), 1.85-1.72 (m, 1H), 1.71-1.66 (m, 1H), 1.50-1.40 (m, 1H); LCMS(APCI+) m/z 406 (M+H)+.

Example 49

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)quinoxaline-2-carboxamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.160 g,0.696 mmol, Example 1, Step H), quinoxaline-2-carboxylic acid (0.254 g,1.46 mmol), BOP-Cl (0.372 g, 1.46 mmol), and triethylamine (0.352 g,3.48 mmol) were placed in DCM (5 mL) at room temperature and stirred for15 hours. 3M aqueous LiOH (3 mL) was then added, and the reaction wasstirred for 10 minutes. Water (10 mL) and DCM (10 mL) were then added,and the reaction was filtered. The resulting solid was slurried with10:1 DCM:MeOH and filtered to give solidN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)quinoxaline-2-carboxamide(0.240 g, 89% yield).

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)quinoxaline-2-carboxamide(0.240 g, 0.621 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.373g, 1.86 mmol) were placed in n-BuOH (3 mL) and heated to 155° C. for 48hours in a sealed tube. The reaction was then cooled to room temperatureand concentrated to dryness. The resulting residue was purified byreverse phase HPLC (5:75 water:ACN gradient. Gilson system) to give(R)-tert-butyl1-(5-bromo-3-(quinoxaline-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.040 g, 11% yield).

Step C: (R)-tert-Butyl1-(5-bromo-3-(quinoxaline-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.040 g, 0.071 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added. The reaction was stirred at room temperature for1 hour and concentrated to dryness to give the crude product, which waspurified by reverse phase HPLC (0-50% ACN in water, Gilson system). Thepurified product was then dissolved in DCM (with minimal MeOH to aidsolubility) and added dropwise to a stirring solution of 1M HCl inether. The resulting solid was filtered, dried and collected to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)quinoxaline-2-carboxamidehydrochloride (0.007 g, 18% yield). LCMS (APCI+) m/z 466, 468(M)+(Method 2).

Example 50

(R)—N-(5-Bromo-4-(3-(isobutylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (0.075 g, 0.14 mmol, Example 1A), DIEA (0.100 mL, 0.57mmol; d 0.742) and trimethyl orthoformate (0.32 mL, 2.9 mmol) wereplaced in MeOH (3 mL) at room temperature. Isobutyraldehyde (0.026 mL,0.29 mmol) was then added, and the reaction was stirred at roomtemperature for 18 hours. NaBH₄ (0.014 g, 0.36 mmol) was then added, andthe reaction was stirred for 1 hour. The reaction was then poured intowater, and extracted with DCM. The combined organic fractions were dried(MgSO₄), filtered, and concentrated to give the crude product, which waspurified by reverse phase HPLC (0-50% acetonitrile (“ACN”) in water,Gilson system). The purified product was then dissolved in DCM (withminimal MeOH to aid solubility) and added dropwise to a stirringsolution of 1M HCl in ether. The resulting solid was filtered, dried andcollected to give(R)—N-(5-bromo-4-(3-(isobutylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (0.050 g, 60% yield). ¹H NMR (400 MHz, D₂O) δ 9.16-9.16(m, 1H), 8.83-8.82 (m, 1H), 8.77-8.75 (m, 1H), 8.27 (s, 1H), 7.96-7.93(m, 1H), 7.42 (s, 1H), 3.78-3.75 (m, 1H), 3.34-3.33 (m, 2H), 3.22-3.17(m, 1H), 3.09-3.03 (m, 1H), 2.77-2.67 (m, 2H), 2.00-1.97 (m, 1H),1.81-1.75 (m, 1H), 1.68-1.65 (m, 1H), 1.52-1.49 (m, 1H), 1.35-1.32 (m,1H), 0.80-0.78 (m, 6H); LCMS (APCI+) m/z 471, 473 (M+H)+.

Example 51

(R)—N-(5-Bromo-4-(3-(cyclopropylmethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (0.075 g, 0.14 mmol, Example 1A), trimethyl orthoformate(0.32 mL, 2.9 mmol), and DIEA (0.100 mL, 0.57 mmol; d 0.742) were placedin MeOH (3 mL). Cyclopropanecarbaldehyde (0.022 mL, 0.29 mmol) was thenadded, and the reaction was stirred at room temperature for 18 hours.NaBH₄ (0.014 g, 0.36 mmol) was then added, and the reaction was stirredfor 1 hour. The reaction was then poured into water, and extracted withDCM. The combined organic fractions were dried (MgSO₄), filtered, andconcentrated to give the crude product, which was purified by reversephase HPLC (0-50% ACN in water, Gilson system). The purified product wasthen dissolved in DCM (with minimal MeOH to aid solubility) and addeddropwise to a stirring solution of 1M HCl in ether. The resulting solidwas filtered, dried and collected to give(R)—N-(5-bromo-4-(3-(cyclopropylmethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride salt (0.050 g, 60% yield). ¹H NMR (400 MHz, D₂O) δ8.98-8.98 (m, 1H), 8.65-8.64 (m, 1H), 8.52-8.50 (m, 1H), 8.12 (s, 1H),7.74-7.71 (m, 1H), 7.27 (s, 1H), 3.54-3.51 (m, 1H), 3.18-3.04 (m, 3H),2.97-2.92 (m, 1H), 2.69-2.55 (m, 2H), 1.82-1.78 (m, 1H), 1.55-1.52 (m,1H), 1.40-1.30 (m, 1H), 1.21-1.17 (m, 1H), 0.74-0.68 (m, 1H), 0.36-0.32(m, 2H), 0.05-0.00 (m, 2H); LCMS (APCI+) m/z 469, 471 (M+H)+.

Example 52

N-(4-((R)-3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-3-carboxamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H), tetrahydrofuran-3-carboxylicacid (202 mg, 1.74 mmol) and triethylamine (606 μL, 4.35 mmol) in CH₂Cl₂(10 mL) at room temperature was treated with BOP-Cl (162 mg, 1.74 mmol).The mixture was stirred for 60 minutes, and the solvent was removed invacuo. The resulting residue was dissolved in THF (10 mL) and treatedwith lithium hydroxide hydrate (109 mg, 2.61 mmol) in water (I mL).After 30 minutes, the mixture was concentrated in vacuo, and water (5mL) was added to the residue. The solid formed was filtered, washed withadditional water and dried to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-3-carboxamide(210 mg, 74% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.07 (brs, 1H), 9.65 (s, 1H), 8.35 (d, 1H), 7.59 (s, 1H), 3.95 (t, 1H),3.81-3.68 (m, 3H), 3.26-3.18 (m, 1H), 2.11-2.05 (m, 2H); LCMS (APCI+)m/z 327.9, 329.9 (M+H)+, Retention time=2.44 min (Method 2).

Step B: A solution ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-3-carboxamide(205 mg, 0.625 mmol) in n-BuOH (5 mL) was treated with (R)-tert-butylpiperidin-3-ylcarbamate (626 mg, 3.12 mmol) and stirred at 160° C. for18 hours in a sealed tube. The solvent was then removed in vacuo, andthe residue was dissolved in EtOAc (50 mL) and washed with water (1×10mL). The organic layer was dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by C-18 flash chromatography (25M+) onBiotage SP4 unit eluting with a gradient of 7-80% CH₃CN/water (25 CV) toprovide tert-butyl(3R)-1-(5-bromo-3-(tetrahydrofuran-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(65 mg, 20% yield). ¹H NMR (400 MHz, CDCl₃) δ 9.65 (s, 1H), 8.78 (br s,1H), 8.26 (s, 1H), 8.02 (s, 1H), 4.54-4.47 (m, 1H), 4.05-3.98 (m, 2H),3.96-3.90 (m, 1H), 3.83-3.72 (m, 1H), 3.70-3.60 (m, 1H), 3.47-3.39 (m,2H), 3.18-3.09 (m, 2H), 3.07-3.00 (m, 1H), 2.41-2.33 (m, 1H), 2.28-2.16(m, 1H), 2.03-1.95 (m, 1H), 1.85-1.74 (m, 2H), 1.42 (s, 9H); LCMS(APCI+) m/z 508.1, 510 (M+H)+, Retention time=3.42 minutes (Method 2).

Step C: A solution of tert-butyl(3R)-1-(5-bromo-3-(tetrahydrofuran-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(57 mg, 0.11 mmol) in neat TFA (5 mL) was stirred at room temperaturefor 30 minutes and concentrated in vacuo. The oily residue was dissolvedin a few drops of CH₂Cl₂ and treated with 2M HCl in Et₂O (3 mL). Thesolid formed was filtered, washed with additional Et₂O and purified byC-18 reverse phase column chromatography (Biotage C-18, 12M+) on BiotageSP4 unit eluting with 5%-60% CH₃CN/water gradient. The product isolatedwas dissolved in few drops of 10% MeOH/CH₂Cl₂ and treated with 2M HCl inEt₂O (4 mL). The precipitate formed was filtered, washed with additionalEt₂O (2×2 mL) followed by CH₃CN (1 mL) and dried to provideN-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-3-carboxamidehydrochloride (20 mg, 37% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.84 (s, 1H), 9.49 (s, 1H), 8.24 (br s, 4H), 7.57 (s, 1H), 3.84-3.71(m, 4H), 3.44-3.36 (m, 3H), 3.28-3.21 (m, 2H), 3.11-3.06 (m, 1H),2.17-2.08 (m, 3H), 1.87-1.80 (m, 1H), 1.76-1.65 (m, 1H), 1.53-1.43 (m,1H); LCMS (APCI+) m/z 408, 410 (M+H)+, Retention time=1.99 minutes(Method 2).

Example 53

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylisoxazole-3-carboxamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H), 5-methylisoxazole-3-carboxylicacid (221 mg, 1.74 mmol) and triethylamine (606 μL, 4.35 mmol) in CH₂C₂(10 mL) at room temperature was treated with BOP-Cl (162 mg, 1.74 mmol).The mixture was stirred at room temperature overnight and additionalBOP-Cl (81 mg, 0.87 mmol) and 5-methylisoxazole-3-carboxylic acid (110mg, 0.87 mmol) were added. The mixture was stirred for an additional 48hours at room temperature. Next, 2M LiOH (3 mL) was added to the mixtureand stirred for 1 hour. The organic solvent was removed in vacuo, andwater:CH₂Cl₂ (11 mL; 10:1) were added to the aqueous residue. The solidformed was filtered, washed with additional water and dried to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylisoxazole-3-carboxamide(210 mg, 71% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.12 (s,1H), 10.22 (s, 1H), 8.33 9d, 1H), 7.58 (s, 1H), 2.45 (s, 3H); LCMS(APCI+) m/z 338.9, 340.9 (M+H)+, Retention time=3.16 minutes (Method 2).

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylisoxazole-3-carboxamide(200 mg, 0.590 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (591 mg,2.95 mmol) in n-BuOH (5 mL) was stirred at 150° C. for 24 hours in asealed tube. The reaction mixture was then concentrated in vacuo, andthe liquid residue was purified by C-18 reverse phase flashchromatography (Biotage C-18 Flash 25M+) on Biotage SP4 unit elutingwith 10-80% CH₃CN/water gradient (24 CV). The product isolated wascrystallized from MeOH/CH₃CN to provide (R)-tert-butyl1-(5-bromo-3-(5-methylisoxazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(40 mg, 13% yield) as a solid. LCMS (APCI+) m/z 519, 521 (M+H)+,Retention time=4.08 minutes (Method 2).

Step C: A solution of (R)-tert-butyl1-(5-bromo-3-(5-methylisoxazole-3-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(38 mg, 0.073 mmol) in neat TFA (2 mL) was stirred at room temperaturefor 30 minutes and concentrated in vacuo. The residue was dissolved in afew drops of CH₂Cl₂ and treated with 2M HCl in Et₂O (2 mL). The solidisolated was purified by C-18 reverse phase chromatography (BiotageC-18, 12M+) on SP4 unit eluting with a gradient of 4-60% CH₃CN/water (14CV). The residue was dissolved in a few drops of CH₂Cl₂, and 2M HCl inEt₂O (2 mL) was added. The precipitate formed was filtered, washed withadditional Et₂O and dried under high vacuum to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylisoxazole-3-carboxamidehydrochloride (11 mg, 28% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.95 (d, 1H), 10.45 (s, 1H), 8.31 (s, 1H), 8.25 (br s, 3H), 7.97 (s,1H), 6.75 (s, 1H), 3.68-3.58 (m, 2H), 3.53-3.45 (m, 1H), 3.36-3.30 (m,1H), 3.08-3.02 (m, 1H), 2.53 (s, 3H), 2.21-2.13 (m, 1H), 2.07-1.96 (m,1H), 1.87-1.81 (m, 1H), 1.55-1.44 (m, 1H); LCMS 402 (APCI+) m/z (M+H)+,Retention time=2.49 minutes (Method 2).

Example 54

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H), 3-methoxypropanoic acid (204.2μL, 2.174 mmol) and triethylamine (605.9 μL, 4.347 mmol) in CH₂Cl₂ (10mL) at room temperature was treated with BOP-Cl (202.7 mg, 2.174 mmol).The mixture was stirred at room temperature for 24 hours. 2M LiOH.H₂O inwater (3 mL) was then added and stirred for 30 minutes. The precipitateformed was filtered, washed with CH₂Cl₂ (3×2 mL), and dried to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide(115 mg, 42% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.05 (brs, 1H), 9.55 (s, 1H), 8.34 (d, 1H), 7.63 (s, 1H), 3.63 (t, 2H), 3.26 (s,3H), 2.58 (t, 2H); LCMS (APCI+) m/z 317.9 (M+H)+, Retention time=2.57minutes (Method 2).

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide(110 mg, 0.348 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (279 mg,1.39 mmol) in n-BuOH (5 mL) was stirred at 160° C. for 24 hours. Themixture was diluted with EtOAc (100 mL) and washed with brine (1×20 mL).The organic layer was separated, dried (MgSO₄), filtered, andconcentrated in vacuo. The residue was purified by C-18 reverse phasechromatography (Biotage 25M+ column) on Biotage SP4 unit eluting with10-85% CH₃CN gradient (25 CV) to provide (R)-tert-butyl1-(5-bromo-3-(3-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamateas a solid. This material was dissolved in TFA (3 mL) and stirred atroom temperature for 20 minutes. TFA was then removed in vacuo, and theresidue was dissolved in a few drops of methanol and purified by C-18reverse phase chromatography (Biotage C-18, 12M+ column) on Biotage SP4unit eluting with 1-50% CH₃CN/water gradient (14 CV). The productisolated was dissolved in CH₂Cl₂ (1 mL), and 2M HCl in ether (2 mL) wasadded. The solid was dissolved in MeOH, evaporated from CH₂Cl₂ (3×2 mL)and dried under high vacuum to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamidehydrochloride (28 mg, 20% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.80 (s, 1H), 9.34 (s, 1H), 8.23 (br s, 4H), 7.57 (br s, 1H), 3.64(t, 2H), 3.55-3.49 (m, 2H), 3.42-3.55 (m, 2H), 3.27 (s, 3H), 3.08-3.03(m, 1H), 2.62 (t, 2H), 2.15-2.09 (m, 1H), 1.88-1.81 (m, 1H), 1.75-1.67(m, 1H), 1.53-1.45 (m, 1H); LCMS (APCI+) m/z 396, 398 (M+H)+, Retentiontime=2.09 minutes (Method 2).

Example 55

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H), 2-methylthiazole-4-carboxylicacid (311 mg, 2.17 mmol), and triethylamine (606 μL, 4.35 mmol) inCH₂Cl₂ (10 mL) at room temperature was treated with BOP-Cl (203 mg, 2.17mmol). After 1 hour the solid formed was filtered and washed with CH₂Cl₂(3×4 mL) to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamide(210 mg, 68% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.14 (s,1H), 9.83 (s, 1H), 8.38 (d, 1H), 8.26 (s, 1H), 7.74 (d, 1H), 2.77 (s,3H); LCMS (APCI+) m/z 354.9, 356.9 (M+H)+, Retention time=3.39 minutes(Method 2).

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamide(200 mg, 0.563 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (338 mg,1.69 mmol) in n-BuOH was stirred at 160° C. in a sealed tube. After 18hours, additional (R)-tert-butyl piperidin-3-ylcarbamate (113 mg, 0.563mmol) was added to the mixture and heating at 160° C. was continued fora further 18 hours. The mixture was concentrated in vacuo and purifiedby C-18 reverse phase column chromatography (Biotage Flash 25 M+ column)on Biotage SP4 unit eluting with a gradient of 10-85% CH₃CN/water (25CV) to provide (R)-tert-butyl1-(5-bromo-3-(2-methylthiazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate.This material was dissolved in neat TFA (3 mL), stirred at roomtemperature for 30 minutes and concentrated in vacuo. The oily residuewas dissolved in a few drops of methanol and treated with 2M HCl inether. The resulting precipitate was concentrated under reducedpressure, and the residue was dissolved in a few drops of methanol andCH₃CN was added. The precipitate formed was filtered and dried underhigh vacuum to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methylthiazole-4-carboxamidehydrochloride (25 mg, 10% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.87 (s, 1H), 10.64 (s, 1H), 8.34 (br s, 3H), 8.31 (s, 1H), 8.28 (s,1H), 8.09 (d, 1H), 3.85-3.24 (m, 1H), 3.70-3.57 (m, 2H), 3.35-3.28 (m,1H), 3.09-3.02 (m, 1H), 2.81 (s, 3H), 2.36-2.27 (m, 2H), 1.94-1.86 (m,1H), 1.63-1.51 (m, 1H); LCMS (APCI+) m/z 435.0, 437.0 (M+H)+, Retentiontime=2.54 minutes (Method 2).

Example 56

(R)—N-(4-(3-Aminopiperidin-1-yl-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclobutanecarboxamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H), cyclobutanecarboxylic acid (218mg, 2.17 mmol) and triethylamine (606 μL, 4.35 mmol) in CH₂Cl₂ (10 mL)at room temperature was treated with BOP-Cl (203 mg, 2.17 mmol). Thereaction was stirred at room temperature for 42 hours. The reactionmixture was then treated with 2M LiOH.H₂O (2 mL) and stirred at roomtemperature for 18 hours. Water (10 mL) was added to the reactionmixture, and the solid formed was filtered, washed with additionalwater, and dried to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclobutanecarboxamide(193 mg, 71% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.04 (brs, 1H), 9.33 (s, 1H), 8.33 (d, 1H), 7.57 (s, 1H), 3.29-3.24 (m, 1H),2.25-2.18 (m, 2H), 2.15-2.08 (m, 2H), 1.98-1.88 (m, 1H), 1.86-1.78 (m,1H); LCMS (APCI+) m/z 311.9, 314.0 (M+H)+, Retention time=2.96 minutes(Method 2).

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclobutanecarboxamide(188 mg, 0.602 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (362 mg,1.81 mmol), and triethylamine (168 μL, 1.20 mmol) in n-BuOH (5 mL) wasstirred at 160° C. in a sealed tube for 18 hours. The mixture wasallowed to cool to room temperature, and was then diluted with EtOAc(100 mL) and washed with brine (2×20 mL). The organic layer wasseparated, dried (MgSO₄), filtered, and concentrated in vacuo. Theliquid residue was purified by C-18 reverse phase chromatography(Biotage 25M+) on Biotage SP4 unit eluting with a gradient of 12-85%CH₃CN/water (25 CV) to provide (R)-tert-butyl1-(5-bromo-3-(cyclobutanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(90 mg, 30% yield) as a solid. This material was dissolved in neat TFA(3 mL) and stirred at room temperature for 30 minutes. The mixture wasthen concentrated in vacuo, and the oily residue was dissolved in a fewdrops of CH₂Cl₂ and treated with 2M HCl in ether. The solid formed wascrystallized from MeOH and CH₃CN to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclobutanecarboxamidehydrochloride (65 mg, 79% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.81 (s, 1H), 9.19 (s, 1H), 8.29 (br s, 3H), 8.23 (s, 1H), 7.59 (s,1H), 3.46-3.37 (m, 2H), 3.35-3.26 (m, 3H), 3.08-3.03 (m, 1H), 2.34-2.24(m, 2H), 2.18-2.11 (m, 3H), 2.01-1.94 (m, 1H), 1.86-1.80 (m, 2H),1.70-1.60 (m, 1H), 1.50-1.44 (m, 1H); LCMS (APCI+) m/z 392, 394 (M+H)+,Retention time=2.28 minutes (Method 2).

Example 57

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H), 3-methylbutanoic acid(isovaleric acid) (222 mg, 2.17 mmol) and triethylamine (606 μL, 4.35mmol) in CH₂Cl₂ (10 mL) was processed as described in Example 56, StepA, to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide(182 mg, 67% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.04 (s,1H), 9.46 (s, 1H), 8.34 (d, 1H), 7.56 (s, 1H), 2.20 (d, 2H), 2.11-2.05(m, 1H), 0.96 (d, 6H); LCMS (APCI+) m/z 314, 316 (M+H)+, Retentiontime=3.02 minutes (Method 2).

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide(177 mg, 0.563 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (339 mg,1.69 mmol), and triethylamine (157 μL, 1.13 mmol) in n-BuOH (5 mL) wasprocessed as in Example 56, Step B, and the crude was purified by C-18reverse phase chromatography (Biotage 25M+) on Biotage SP4 unit elutingwith a gradient of 15-85% CH₃CN/water (25 CV) to provide (R)-tert-butyl1-(5-bromo-3-(3-methylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(109 mg, 39% yield) as a solid. LCMS (APCI+) m/z 494, 496 (M+H)+,Retention time=3.92 minutes (Method 2).

Step C: A solution of (R)-tert-butyl1-(5-bromo-3-(3-methylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(97 mg, 0.20 mmol) in neat TFA (4 mL) was stirred at room temperaturefor 30 minutes. TFA was removed in vacuo, and the residue was dissolvedin few drops of methanol and treated with 2M HCl in ether (2 mL). Theresulting precipitate was concentrated in vacuo, and the oily residueobtained was evaporated from CH₃CN (3×5 mL). The residue obtained wastriturated with CH₃CN. The resulting solid was filtered, washed withadditional CH₃CN, and dried under high vacuum to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamidehydrochloride (89 mg, 97% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.76 (s, 1H), 9.24 (s, 1H), 8.24 (br s, 3H), 8.17 (s, 1H), 7.50 (s,1H), 3.41-3.34 (m, 2H), 3.29-3.20 (m, 2H), 3.05-2.99 (m, 1H), 2.21 (d,2H), 2.10-2.03 (m, 2H), 1.82-1.76 (m, 1H), 1.67-1.61 (m, 1H), 1.48-1.39(m, 1H), 0.92 (d, 6H); LCMS (APCI+) m/z 394, 396 (M+H)+, Retentiontime=2.26 minutes (Method 2).

Example 58

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H), 2-cyclopropylacetic acid (218mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP-Cl (203 mg,2.17 mmol) in CH₂Cl₂ (10 mL) was stirred at room temperature for 42hours. Then 2M LiOH.H₂O (3 mL) was added, and the mixture was stirredfor 18 hours. The mixture was then diluted with CH₂Cl₂ (50 mL). Thelayers were separated, and the organic layer was dried (MgSO₄),filtered, and concentrated in vacuo to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide(204 mg, 75% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.04 (s,1H), 9.40 (s, 1H), 8.34 (d, 1H), 7.61 (s, 1H), 2.24 (d, 2H), 1.10-1.03(m, 1H), 0.52-0.47 (m, 2H), 0.24-0.20 (m, 1H); LCMS (APCI+) m/z (M+H)+,Retention time=2.92 minutes (Method 2).

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide(204 mg, 0.654 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (393 mg,1.96 mmol), and triethylamine (182 μL, 1.31 mmol) in n-BuOH (5 mL) wasprocessed as in Example 56. The crude was purified by C-18 reverse phasechromatography (Biotage 25M+) on Biotage SP4 unit eluting with agradient of 15-85% CH₃CN/water (25 CV) to provide (R)-tert-butyl1-(5-bromo-3-(2-cyclopropylacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(85 mg, 26% yield) as a solid. LCMS (APCI+) m/z 492, 494 (M+H)+,Retention time=3.75 min (Method 2).

Step C: A solution of (R)-tert-butyl1-(5-bromo-3-(2-cyclopropylacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(80 mg, 0.16 mmol) in neat TFA (3 mL) was stirred at room temperaturefor 30 minutes. TFA was then removed in vacuo. The oily residue obtainedwas dissolved in few drops of CH₂Cl₂ and treated with 2M HCl in ether (2mL). The solid formed was filtered, washed with additional CH₂Cl₂ (3×3mL). This material was dissolved in MeOH (0.5 mL), and CH₃CN was addeduntil the mixture became cloudy. The mixture was allowed to stand atroom temperature. The solid formed was filtered, washed with additionalCH₃CN (2×2 mL), was dried under a stream of nitrogen first and thenunder high vacuum to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamidehydrochloride (32 mg, 42% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.81 (s, 1H), 9.25 (s, 1H), 8.23 (s, 1H), 8.22 (br s, 3H), 7.54 (s,1H), 3.45-3.38 (m, 2H), 3.36-3.26 (m, 2H), 3.10-3.04 (m, 1H), 2.31 (d,2H), 2.15-2.08 (m, 1H), 1.86-1.79 (m, 1H), 1.72-1.62 (m, 1H), 1.53-1.45(m, 1H), 1.13-1.06 (m, 1H), 0.54-0.51 (m, 2H), 0.24-0.21 (m, 2H); LCMS(APCI+) m/z 392.1, 394 (M+H)+, Retention time=2.23 minutes (Method 2).

Example 59

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-ethylbutanamide

Step A: A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H) in pyridine at 0° C. was treateddropwise with 2-ethylbutanoyl chloride (176 mg, 1.30 mmol). After 7hours, 2M LiOH (5 mL) was added to the mixture and stirring wascontinued at room temperature for 30 minutes. Water (25 mL) was thenadded, and the solid formed was filtered, washed with water (3×5 mL) anddried to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-ethylbutanamide(235 mg, 82% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.06 (s,1H), 9.46 (s, 1H), 8.34 (d, 1H), 7.53 (s, 1H), 2.30-2.24 (m, 1H),1.62-1.52 (m, 2H), 1.47-1.41 (m, 2H), 0.90 (t, 6H); LCMS (APCI+) m/z328, 330 (M+H)+, Retention time=3.20 minutes (Method 2).

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-ethylbutanamide(225 mg, 0.686 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (412 mg,2.06 mmol), and N-ethyl-N-isopropylpropan-2-amine (239 μL, 1.37 mmol) inn-BuOH (5 mL) was purged under N₂ and stirred at 160° C. in a sealedtube for 16 hours. The solvent was then removed in vacuo, and the liquidresidue was purified by C-18 reverse phase column chromatography(Biotage Flash 25M+; C-18) on Biotage SP4 unit eluting with a gradientof 15-90% CH₃CN/water (25 CV) to provide (R)-tert-butyl1-(5-bromo-3-(2-ethylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(201 mg, 58% yield) as a solid. LCMS (APCI+) m/z 508, 510 (M+H)+,Retention time=4.15 minutes (Method 2).

Step C: A solution of (R)-tert-butyl1-(5-bromo-3-(2-ethylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(170 mg, 0.334 mmol) in neat TFA (4 mL) was stirred at room temperaturefor 30 minutes. TFA was then removed in vacuo, and the oily residue wasdissolved in CH₂Cl₂ and treated with 2M HCl in Et₂O. The resultingsuspension was concentrated in vacuo and evaporated from CH₃CN (3×5 mL).The solid residue obtained was triturated with CH₃CN, filtered, washedwith additional CH₃CN and dried under high vacuum to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-ethylbutanamidehydrochloride (125 mg, 78% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.79 (s, 1H), 9.28 (s, 1H), 8.35 (br s, 3H), 8.25 (s, 1H), 7.71 (brs, 1H), 3.65-3.53 (m, 1H), 3.45-3.37 (m, 2H), 3.36-3.27 (m, 1H),3.13-3.05 (m, 1H), 2.22-2.13 (m, 2H), 1.97-1.86 (m, 1H), 1.70-1.58 (m,3H), 1.56-1.47 (m, 3H), 0.93-0.88 (m, 6H); LCMS (APCI+) m/z 408, 410(M+H)+, Retention time=2.33 minutes (Method 2).

Example 60

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H), 2-methyloxazole-4-carboxylicacid (276 mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP-Cl(203 mg, 2.17 mmol) in CH₂Cl₂ (10 mL) was stirred at room temperaturefor 4 hours. Next, 2M LiOH.H₂O (3 mL) was added, and after 30 minuteswater (10 mL) was added. The solid formed was filtered, washed withwater (2×5 mL) and dried to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide(165 mg, 56% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.15 (s,1H), 9.68 (s, 1H), 8.63 (s, 1H), 8.37 (d, 1H), 7.67 (s, 1H), 2.52 (s,3H); LCMS (APCI+) m/z 338.9, 341.0 (M+H)+, Retention time=3.21 minutes(Method 2).

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamide(160 mg, 0.472 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (378 mg,1.89 mmol) in n-BuOH (3 mL) was stirred at 160° C. in a sealed tube. Themixture was allowed to cool to room temperature and concentrated invacuo. The residue was dissolved in MeOH (1 mL) and purified by C-18reverse phase flash chromatography (Biotage Flash 25 M+) on SP4 uniteluting with 10-85% CH₃CN/water gradient (25 CV) to provide(R)-tert-butyl1-(5-bromo-3-(2-methyloxazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamateas a solid. This material was treated with neat TFA (3 mL), and after 30minutes the mixture was concentrated in vacuo. The residue obtained wasdissolved in few drops of CH₂Cl₂ and treated with 2M HCl in ether (3mL). The solid formed was filtered, washed with additional Et₂₀ anddried under high vacuum to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methyloxazole-4-carboxamidehydrochloride (23 mg, 12% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.85 (s, 1H), 10.41 (s, 1H), 8.68 (s, 1H), 8.30 (s, 1H), 8.27 (br s,3H), 8.02 (s, 1H), 4.01-3.99 (m, 1H), 3.69-3.63 (m, 1H), 3.60-3.52 (m,1H), 3.36-3.29 (m, 1H), 3.06-2.99 (m, 1H), 2.58 (s, 3H), 2.34-2.25 (m,2H), 1.89-1.82 (m, 1H), 1.59-1.51 (m, 1H); LCMS (APCI+) m/z 419, 421(M+H)+, Retention time=2.44 minutes (Method 2).

Example 61

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide

Step A: 2-Methoxyacetyl chloride (0.074 mL, 0.76 mmol) was added to asolution of4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (120 mg,0.51 mmol, Example 12, Steps A-G) in pyridine (5 mL) at 0° C. Thereaction was stirred at 0° C. for 10 minutes, and the pyridine wasremoved in vacuo. The residue obtained was dissolved in THF (5 mL),treated with 2N LiOH (3 mL) and stirred for 20 minutes. THF was thenremoved under reduced pressure, and the aqueous slurry obtained wasextracted with water (20 mL) and ethyl acetate (50 mL). The organiclayer was separated, washed with brine, dried (Na₂SO₄) and concentratedin vacuo to provideN-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide(154 mg, 98% yield) as a solid.

Step B: A mixture ofN-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide(154 mg, 0.501 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (301 mg,1.50 mmol) and DIEA (0.17 mL, 1.00 mmol) in NMP (2 mL) was stirred at156° C. for 10 hours. The solvent was removed in vacuo. The residueobtained was dissolved in ethyl acetate (20 mL), washed with water (10mL) and followed by brine (10 mL). The organic layer was separated,dried (Na₂SO₄), and concentrated in vacuo. The residue obtained waspurified by C-18 reverse phase flash chromatography (Biotage SP4 unit,C-18, 25M+ column, 30-70% CH₃CN/water gradient; 30 CV). The solidisolated was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. Themixture was stirred at room temperature for 1 hour, and the solvent wasremoved in vacuo. The resulting residue was dissolved in DCM (1 mL) andtreated with 2N HCl in ether (3 mL). The solid formed was collected byfiltration and dried to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamidehydrochloride (61 mg, 27% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.42 (s, 1H), 7.52 (s, 1H), 4.12 (s, 2H), 3.40 (s, 3H), 3.38 (m, 2H),2.96 (m, 3H), 2.00 (m, 1H), 1.73 (m, 1H), 1.68 (m, 1H), 1.54 (m, 1H);LCMS (APCI+) m/z 372 (M+H)+.

Example 62

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide

Step A: A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H), 3-chloro-4-fluorobenzoic acid(319 mg, 1.83 mmol), BOP-Cl (465 mg, 1.83 mmol), and triethylamine(0.606 mL, 4.35 mmol) in DCM (5 mL) at room temperature was stirred for2 hours. 3M aqueous LiOH (3 mL) was then added, and the mixture wasstirred for 10 minutes. Next, water (10 mL) and DCM (10 mL) were added,and the resulting precipitate was filtered. The solid isolated wastriturated with 10:1 CH₂Cl₂:MeOH and filtered to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide(240 mg, 71% yield) as a solid.

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide(240 mg, 0.621 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (373 mg,1.86 mmol) in n-BuOH (3 mL) was stirred at 155° C. for 16 hours in asealed tube. The reaction was then cooled to room temperature andconcentrated in vacuo. The resulting residue was purified by reversephase HPLC (Gilson) to provide (R)-tert-butyl1-(5-bromo-3-(3-chloro-4-fluorobenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(110 mg, 31% yield).

Step C: A solution of (R)-tert-butyl1-(5-bromo-3-(3-chloro-4-fluorobenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(110 mg, 0.194 mmol) in DCM (3 mL) was treated with TFA (1 mL) at roomtemperature for 1 hour. The mixture was then concentrated in vacuo. Theresulting residue was dissolved in a minimal amount of DCM and added toa stirring solution of 1M HCl in ether. The solid obtained was filtered,washed with ether and dried to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamidehydrochloride (80 mg, 76% yield). ¹H NMR (400 MHz, D₂O) δ 8.22 (s, 1H),7.97-7.94 (m, 1H), 7.80-7.77 (m, 1H), 7.38 (s, 1H), 7.32-7.28 (m, 1H),3.54-3.52 (m, 1H), 3.32-3.30 (m, 1H), 3.25-3.21 (m, 1H), 3.18-3.10 (m,2H), 1.88-1.80 (m, 1H), 1.68-1.63 (m, 1H), 1.50-1.33 (m, 2H); LCMS(APCI+) m/z 466, 486 (M+H)+.

Example 63

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoro-4-methoxybenzamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.87 mmol, Example 1, Step H), 3-fluoro-4-methoxybenzoic acid(311 mg, 1.83 mmol), BOP-Cl (0.465 g, 1.83 mmol), and triethylamine(0.606 mL, 4.35 mmol) in DCM (5 mL) was processed as described inExample 62, Step A, to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoro-4-methoxybenzamide(300 mg, 90% yield) as a solid. LCMS (APCI+) m/z 381.9, 383.9 (M+H)+,Retention time=3.23 minutes (Method 2).

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoro-4-methoxybenzamide(300 mg, 0.785 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (472 mg,2.36 mmol) in n-BuOH (3 mL) was stirred at 155° C. for 16 hours in asealed tube. The reaction was then cooled to room temperature andconcentrated in vacuo. The resulting residue was purified by reversephase HPLC (Gilson) to provide (R)-tert-butyl1-(5-bromo-3-(3-fluoro-4-methoxybenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(120 mg, 27% yield).

Step C: (R)-tert-Butyl1-(5-bromo-3-(3-fluoro-4-methoxybenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(150 mg, 0.27 mmol) in DCM (3 mL) was treated with TFA (1 mL), followedby 1M HCl in ether according to the procedure described in Example 62,Step C, to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoro-4-methoxybenzamidehydrochloride (90 mg, 63% yield). ¹H NMR (400 MHz, D₂O) δ 8.20 (s, 1H),7.67-7.64 (m, 1H), 7.62-7.59 (m, 1H), 7.35 (s, 1H), 7.18-7.14 (m, 1H),3.84 (s, 3H), 3.46-3.40 (m, 1H), 3.28-3.18 (m, 2H), 3.12-3.09 (m, 2H),1.79-1.74 (m, 1H), 1.68-1.61 (m, 1H), 1.46-1.30 (m, 2H); LCMS (APCI+)m/z 462, 464 (M+H)+.

Example 64

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazole-4-carboxamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(300 mg, 1.30 mmol, Example 1, Step H),1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylic acid (636 mg, 2.74 mmol),BOP-Cl (697 mg, 2.74 mmol), and triethylamine (0.909 mL, 6.52 mmol) inDCM (5 mL) was processed as described in Example 62, Step A, to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide(230 mg, 39% yield).

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide(230 mg, 0.518 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (311 mg,1.55 mmol) in n-BuOH (2.5 mL) was heated to 155° C. for 48 hours in asealed tube. The reaction mixture was then cooled to room temperatureand concentrated in vacuo. The resulting residue was purified by reversephase HPLC (Gilson) to provide (R)-tert-butyl1-(5-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(60 mg, 18% yield).

Step C: A solution of (R)-tert-butyl1-(5-bromo-3-(1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(120 mg, 0.192 mmol) in DCM (3 mL) was treated with TFA (1 mL) at roomtemperature for 30 minutes. The reaction was then concentrated in vacuoand azeotroped with toluene. The resulting residue was dissolved in neatTFA (5 mL) and stirred at 65° C. for 1 hour. The reaction mixture wasthen concentrated in vacuo, and the residue obtained was purified byreverse phase HPLC (Gilson) to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrazole-4-carboxamidehydrochloride (50 mg, 50% yield). ¹H NMR (400 MHz, D₂O) δ 8.26 (s, 1H),8.12 (s, 2H), 7.33 (s, 1H), 3.67-3.63 (m, 1H), 3.41-3.37 (m, 1H),3.30-3.27 (m, 1H), 3.19-3.10 (m, 2H), 1.90-1.83 (m, 1H), 1.68-1.65 (m,1H), 1.55-1.51 (m, 1H), 1.36-1.34 (m, 1H); LCMS (APCI+) m/z 404, 406(M+H)+.

Example 65

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethyl)benzamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H), 3-(trifluoromethyl)benzoic acid(347 mg, 1.83 mmol), BOP-Cl (465 mg, 1.83 mmol), and triethylamine(0.606 mL, 4.35 mmol) in DCM (5 mL) was processed as described inExample 62, Step A, to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethyl)benzamide(250 mg, 71% yield) as a solid.

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethyl)benzamide(250 mg, 0.622 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (374 mg,1.87 mmol) in n-BuOH (3 mL) was processed as described in Example 62,Step B, to provide (R)-tert-butyl1-(5-bromo-3-(3-(trifluoromethyl)benzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(250 mg, 69% yield).

Step C: (R)-tert-Butyl1-(5-bromo-3-(3-(trifluoromethyl)benzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(150 mg, 0.258 mmol) was treated with TFA (1 mL) followed by 1M HCl asdescribed in Example 62, Step C, to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethyl)benzamidehydrochloride (0.130 g, 91% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.24 (s, 1H), 8.12 (s, 1H), 8.05-8.04 (d, 1H), 7.88-7.86 (d, 1H),7.66-7.62 (m, 1H), 7.42 (s, 1H), 3.63-3.60 (m, 1H), 3.36-3.32 (m, 1H),3.22-3.17 (m, 2H), 3.13-3.08 (m, 1H), 1.84-1.81 (m, 1H), 1.65-1.61 (m,1H), 1.45-1.42 (m, 1H), 1.34-1.31 (m, 1H); LCMS (APCI+) m/z 482, 484(M+H)+.

Example 66

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylpyrazine-2-carboxamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(300 mg, 1.30 mmol, Example 1, Step H), 5-methylpyrazine-2-carboxylicacid (378 mg, 2.74 mmol), BOP-Cl (697 mg, 2.74 mmol), and triethylamine(0.909 mL, 6.52 mmol) in DCM (5 mL) was processed as described inExample 62, Step A, to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylpyrazine-2-carboxamide(280 mg, 61% yield).

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylpyrazine-2-carboxamide(280 mg, 0.800 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (480 mg,2.40 mmol) in n-BuOH (3 mL) was processed as described in Example 62,Step B, to provide crude (R)-tert-butyl1-(5-bromo-3-(5-methylpyrazine-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamatewithout HPLC purification.

Step C: A solution of crude (R)-tert-butyl1-(5-bromo-3-(5-methylpyrazine-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(75 mg, 0.14 mmol) in DCM (3 mL) was treated with TFA (1 mL) at roomtemperature. After 1 hour, the mixture was concentrated in vacuo. Theresulting residue was dissolved in a minimal amount of DCM and added toa stirring solution of 1M HCl in ether. The resulting solid wasfiltered, washed with ether and dried to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methylpyrazine-2-carboxamidehydrochloride (40 mg, 56% yield). ¹H NMR (400 MHz, D₂O) δ 8.47 (s, 1H),8.30 (s, 1H), 8.08 (s, 1H), 7.56 (s, 1H), 3.61-3.59 (m, 1H), 3.51-3.46(m, 1H), 3.42-3.36 (m, 1H), 3.31-3.30 (m, 1H), 2.87-2.84 (m, 1H), 2.40(s, 3H), 2.16-2.13 (m, 1H), 1.90-1.87 (m, 1H), 1.74-1.71 (m, 1H),1.49-1.46 (m, 1H); LCMS (APCI+) m/z 430, 432 (M+H)+.

Example 67

(R)—N-(5-bromo-4-(3-(2-hydroxyethylaminopiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide

Step A: 2-(tert-Butyldimethylsilyloxy)acetaldehyde (0.037 mL, 0.19 mmol)was added to a mixture of(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide(70 mg, 0.13 mmol, Example 62), DIEA (0.068 mL, 0.39 mmol), andtrimethyl orthoformate (280 mg, 2.6 mmol) in MeOH (3 mL), and thereaction was stirred at room temperature for 18 hours. NaBH₄ (9.8 mg,0.26 mmol) was then added, and the reaction was stirred for 1 hour. Themixture was poured into a saturated solution of NaHCO₃, and extractedwith CH₂Cl₂. The combined organic fractions were dried (MgSO₄),filtered, and concentrated in vacuo. The residue obtained was purifiedby column chromatography on silica gel eluting with 2% MeOH:CH₂Cl₂ toprovide(R)—N-(5-bromo-4-(3-(2-(tert-butyldimethylsilyloxy)ethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide(32 mg, 39% yield).

Step B: A solution of(R)—N-(5-bromo-4-(3-(2-(tert-butyldimethylsilyloxy)ethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide(30 mg, 0.048 mmol) in THF (2 mL) at room temperature was treated withTBAF (0.048 mL, 0.048 mmol) and stirred for 10 minutes. The mixture wasthen concentrated in vacuo and purified by reverse phases HPLC (Gilson).The residue obtained was dissolved in a minimal amount of DCM and addedto a stirring solution of 1M HCl in ether. The solid formed wasfiltered, washed with ether and dried to give(R)—N-(5-bromo-4-(3-(2-hydroxyethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamidehydrochloride (0.015 g, 54% yield). ¹H NMR (400 MHz, D₂O) δ 8.19 (s,1H), 7.98-7.94 (m, 1H), 7.82-7.76 (m, 1H), 7.38 (s, 1H), 7.34-7.29 (m,1H), 3.64-3.61 (m, 2H), 3.42-2.94 (m, 7H), 1.90-1.82 (m, 1H), 1.70-1.62(m, 1H), 1.44-1.36 (m, 2H); LCMS (APCI+) m/z 510, 512 (M+H)+.

Example 68

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-5-methylbenzamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol, Example 1, Step H), 2-fluoro-5-methylbenzoic acid(281 mg, 1.83 mmol), BOP-Cl (465 mg, 1.83 mmol), and triethylamine(0.606 mL, 4.35 mmol) in DCM (5 mL) was processed as described inExample 62, Step A, to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-5-methylbenzamide(200 mg, 63% yield).

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-5-methylbenzamide(208 mg, 0.568 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (341 mg,1.70 mmol) in n-BuOH (2 mL) was processed as described in Example 62,Step B, to provide (R)-tert-butyl1-(5-bromo-3-(2-fluoro-5-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(120 mg, 39% yield).

Step C: A solution of (R)-tert-butyl1-(5-bromo-3-(2-fluoro-5-methylbenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(120 mg, 0.22 mmol) in DCM (3 mL) was treated with TFA followed by 1MHCl as described in Example 62, Step C, to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-5-methylbenzamidehydrochloride (0.070 g, 61% yield). ¹H NMR (400 MHz, D₂O) δ 8.17 (s,1H), 7.50-7.48 (m, 1H), 7.45 (s, 1H), 7.33-7.30 (m, 1H), 7.09-7.04 (m,1H), 3.50-3.48 (m, 1H), 3.31-3.29 (m, 2H), 3.18-3.13 (m, 1H), 3.06-3.03(m, 1H), 1.86-1.82 (m, 1H), 1.68-1.64 (m, 1H), 1.43-1.41 (m, 2H); LCMS(APCI+) m/z 446, 448 (M+H)+.

Example 69

N-(5-bromo-4-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (180 mg,0.537 mmol, Example 1, Step I), tert-butylhexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate hydrochloride (334 mg,1.34 mmol), and DIEA (0.234 mL, 1.34 mmol) in n-BuOH (2 mL) was stirredat 140° C. for 5 hours in a sealed tube. The reaction was then cooled toroom temperature and concentrated in vacuo. The residue obtained waspurified by reverse phase HPLC (Gilson) to provide tert-butyl5-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate (50 mg, 18% yield).

Step B: A solution of tert-butyl5-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)hexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate(0.070 g, 0.13 mmol) in DCM (3 mL) was treated with TFA (1 mL) followedby 1M HCl in ether as described in Example 62, Step C, to provideN-(5-bromo-4-(hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (20 mg, 28% yield). ¹H NMR (400 MHz, D₂O) δ 9.15 (s, 1H),8.84-8.83 (m, 1H), 8.78-8.75 (m, 1H), 8.24 (s, 1H), 8.00-7.96 (m, 1H),7.43 (s, 1H), 4.15-4.11 (m, 1H), 3.97-3.92 (m, 1H), 3.73-3.69 (m, 1H),3.65-3.61 (m, 1H), 3.54-3.50 (m, 1H), 3.27-3.23 (m, 2H), 2.91-2.87 (m,1H), 2.00-2.94 (m, 1H), 1.88-1.86 (m, 1H); LCMS (APCI+) m/z 427, 429(M+H)+.

Example 70

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide

Step A: Picolinoyl chloride hydrochloride (501 mg, 2.82 mmol) was addedto a solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (324mg, 1.41 mmol, Example 1, Step H) in pyridine (5 mL). The reaction wasstirred at room temperature for 10 minutes, and the pyridine was removedin vacuo. The residue obtained was dissolved in THF (5 mL), treated with2N LiOH (3 mL), and stirred for 20 minutes. THF was then removed invacuo, and water (20 mL) was added. The solid formed was collected byfiltration and dried to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide (389 mg,82% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.17 (br s, 1H),10.39 (s, 1H), 8.76 (d, 1H), 8.40 (d, 1H), 8.17-8.15 (m, 1H), 8.09 (dt,1H), 7.87 (d, 1H), 7.71-7.68 (m, 1H).

Step B: N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide(194 mg, 0.579 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.348g, 1.74 mmol) in n-BuOH (2 mL) was stirred at 149° C. for 24 hours in asealed tube and concentrated in vacuo. The residue obtained wasdissolved in ethyl acetate (20 mL) and successively washed with water(10 mL) and brine (10 mL). The organic layer was dried (MgSO₄),filtered, and concentrated in vacuo. The residue obtained was purifiedby C-18 reverse phase column chromatography (Biotage Flash 25M+) onBiotage SP4 unit eluting with gradient of 10-90% CH₃CN/water to provide(R)-tert-butyl1-(5-bromo-3-(picolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate.This material was dissolved in DCM (3 mL), treated with TFA (0.5 mL) andstirred at room temperature for 1 hour. The mixture was thenconcentrated in vacuo. The resulting residue was dissolved in DCM (1 mL)and treated with 2N HCl in ether (3 mL). The solid formed was collectedby filtration and dried to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamidehydrochloride (0.022 g, 0.0419 mmol, 7% yield) as a solid. ¹H NMR (400MHz, (CD₃)₂SO) δ 11.90 (br s, 1H), 11.35 (br s, 1H), 8.87 (d, 1H), 8.36(br s, 3H), 8.31 (s, 1H), 8.21-8.11 (m, 3H), 7.74 (t, 1H), 4.04-3.94 (m,1H), 3.76-3.67 (m, 1H), 3.58-3.48 (m, 1H), 3.43-3.34 (m, 1H), 3.08-3.00(m, 1H), 2.44-2.37 (m, 1H), 2.27-2.14 (m, 1H), 1.90-1.81 (m, 1H),1.63-1.51 (m, 1H); LCMS (APCI+) m/z 415.1, 417 (M+H)+.

Example 71A

(S)—N-(4-((R)-3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol), (S)-tetrahydrofuran-2-carboxylic acid (252 mg,2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP-Cl (203 mg, 2.17mmol) in CH₂Cl₂ (10 mL) was stirred at room temperature for 7 hours. 2MLiOH (5 mL) was added then to the mixture and stirred at roomtemperature for 30 minutes. Water (25 mL) was then added and stirred foran additional 30 minutes. The solid formed was filtered, washed withwater (3×5 mL) and dried to provide(S)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide(202 mg, 70.8% yield) as a solid. LCMS (APCI+) m/z 327.9, 329.9 (M+H)+;Retention time=2.80 minutes (Method 2).

Step B: A mixture of(S)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide(195 mg, 0.594 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (357 mg,1.78 mmol), and N-ethyl-N-isopropylpropan-2-amine (207 μL, 1.19 mmol) inn-BuOH (5 mL) were purged under N₂ and stirred at 160° C. in a sealedtube for 16 hours. The solvent was then removed in vacuo, and theresidue obtained was purified by C-18 reverse phase columnchromatography (Biotage Flash 25M+; C-18) on Biotage SP4 unit elutingwith a gradient of 15-90% CH₃CN/water (25 CV) to provide tert-butyl(R)-1-(5-bromo-3-((S)-tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(150 mg, 0.295 mmol, 49.6% yield) as a solid. LCMS (APCI+) m/z 508.1,510.1 (M+H)+; Retention time=3.85 minutes (Method 2).

Step C: A solution of tert-butyl(R)-1-(5-bromo-3-((S)-tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(150 mg, 0.295 mmol) in neat TFA (3 mL) was stirred at room temperaturefor 30 minutes and concentrated in vacuo. The resulting residue waspurified by C-18 reverse phase flash chromatography (Biotage C-18, 12M+)on Biotage SP4 unit eluting with a gradient of 1-50% CH₃CN/watergradient (14 CV). The product obtained was dissolved in minimal MeOH,diluted with CH₂Cl₂ (1 mL), and treated with 1M HCl in ether (3 mL). Theresulting suspension was concentrated in vacuo and evaporated fromCH₂Cl₂ (3×5 mL). The solid obtained was dried under high vacuum toprovide(S)—N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamidehydrochloride (117 mg, 0.243 mmol, 82.4% yield) as a solid. NMR (400MHz, (CD₃)₂SO) δ 11.72 (s, 1H), 9.82 (s, 1H), 8.29 (br s, 3H), 8.21 (s,1H), 7.89 (s, 1H), 4.39 (t, 1H), 4.02-3.97 (m, 1H), 3.85-3.79 (m, 2H),3.63-3.55 (m, 1H), 3.42-3.35 (m, 1H), 3.33-3.21 (m, 2H), 2.97-2.89 (m,1H), 2.27-2.19 (m, 1H), 2.17-2.09 (m, 1H), 1.97-1.92 (m, 1H), 1.89-1.83(m, 2H), 1.79-1.73 (m, 1H), 1.491.40 (m, 1H); LCMS (APCI+) m/z 408,410.1 (M+H)+; Retention time=2.18 minutes (Method 2).

Example 71B

(R)—N-(4-((R)-3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol), tetrahydrofuran-2-carboxylic acid (252 mg, 2.17mmol), triethylamine (606 μL, 4.35 mmol), and BOP-Cl (203 mg, 2.17 mmol)in CH₂Cl₂ (10 mL) was stirred at room temperature for 7 hours. 2M LiOH(5 mL) was then added to the mixture and stirred at room temperature for30 minutes. Water (25 mL) was then added to the mixture and stirred foran additional 30 minutes. The solid formed was filtered, washed withwater (3×5 mL) and dried to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide(230 mg, 80.6% yield) as a solid.

Step B: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide(225 mg, 0.686 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (412 mg,2.06 mmol), and N-ethyl-N-isopropylpropan-2-amine (239 μL, 1.37 mmol) inn-BuOH (5 mL) was purged under N₂ and stirred at 160° C. in a sealedtube for 16 hours. The solvent was then removed in vacuo, and theresidue obtained was purified by C-18 reverse phase columnchromatography (Biotage Flash 25M+; C-18) on Biotage SP4 unit elutingwith a gradient of 15-90% CH₃CN/water (25 CV) to provide tert-butyl(3R)-1-(5-bromo-3-(tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(101 mg, 0.199 mmol, 29.0% yield) as a solid.

Step C: A solution of tert-butyl(3R)-1-(5-bromo-3-(tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamatein TFA (3 mL) was stirred at room temperature for 30 minutes and thenconcentrated in vacuo. The residue obtained was purified by C-18 reversephase chromatography (Biotage Flash 12 M+, C-18) on Biotage SP4 uniteluting with a gradient of 1-50% CH₃CN/water (14 CV). The pure fractionscontaining the R-isomer (by comparing the retentions times of S-isomer,Example 71A) were pooled, concentrated in vacuo and evaporated fromCH₃CN (3×5 mL). The solid residue obtained was dissolved in minimalmethanol, diluted with CH₂Cl₂ (1 mL) and treated with 2M HCl in ether (3mL). The resulting suspension was concentrated in vacuo and evaporatedfrom CH₂Cl₂ (3×5 mL) and dried under high vacuum for 24 hours to provide(R)—N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamidehydrochloride (16 mg, 21% yield) as a solid. NMR (400 MHz, (CD₃)₂SO) δ11.72 (s, 1H), 9.83 (s, 1H), 8.21 (s, 1H), 8.16 (br s, 3H), 7.89 (s,1H), 4.37 (t, 1H), 3.96-3.91 (m, 1H), 3.85-3.79 (m, 1H), 3.55-3.48 (m,3H), 3.26-3.20 (m, 1H), 2.97-2.91 (m, 1H), 2.28-2.20 (m, 1H), 2.15-2.09(m, 1H), 1.94-1.81 (m, 5H), 1.48-1.40 (m, 1H); LCMS (APCI+) m/z 408.1,410.1 (M+H)+, Retention time=2.32 minutes (Method 2).

Example 72

N-(4-((R)-3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)morpholine-2-carboxamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(350 mg, 1.52 mmol), 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid(739 mg, 3.20 mmol), BOP-Cl (813 mg, 3.20 mmol), and triethylamine (1.06mL, 7.61 mmol) in DCM (5 mL) was stirred at room temperature for 1 hour.3M LiOH (3 mL) was then added, and stirred for an additional 10 minutes.Water (10 mL) and DCM (10 mL) were then added, and the solid formed wasfiltered. The solid product was washed with DCM (10 mL) and dried togive tert-butyl2-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylate(660 mg, 97.9% yield).

Step B: A mixture of tert-butyl2-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylate(660 mg, 1.49 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (1.49 g,7.44 mmol), and DIEA (1.30 mL, 7.44 mmol) in n-BuOH (6 mL) was stirredat 120° C. for 36 hours. The reaction was then cooled to roomtemperature and concentrated in vacuo. The crude residue was purified byreverse phase HPLC (0-50% CH₃CN/water) to give the separateddiastereomers of tert-butyl2-(5-bromo-4-((R)-3-(tert-butoxycarbonylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylatein the following yields: diastereomer #1 (70 mg, 7.5%) diastereomer #2(80 mg, 8.6%).

Step C: A solution of tert-butyl2-(5-bromo-4-((R)-3-(tert-butoxycarbonylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylatediastereomer #1 (70 mg, 0.11 mmol) in DCM (3 mL) at room temperature wastreated with TFA (1 mL), and the reaction was stirred for 1 hour. Themixture was concentrated to dryness, and the resulting residue waspurified by reverse phase HPLC (0-50% ACN in water). The productisolated was dissolved in minimal DCM (with MeOH to aid solubility) andadded to a stirring solution of 1M HCl in ether. The resulting solid wasfiltered, washed with ether and dried to giveN-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)morpholine-2-carboxamidehydrochloride diastereomer #1 (50 mg, 84% yield). ¹H NMR (400 MHz, D₂O)δ 8.18 (s, 1H), 7.59 (s, 1H), 4.54-4.48 (m, 1H), 4.21-4.17 (m, 1H),3.98-3.91 (m, 1H), 3.67-3.64 (m, 1H), 3.47-3.31 (m, 5H), 3.20-3.13 (m,2H), 3.09-2.98 (m, 1H), 2.11-2.07 (m, 1H), 1.80-1.76 (m, 2H), 1.55-1.53(m, 1H); LCMS (APCI+) m/z 423, 425 (M+H)+.

Step D: A solution of tert-butyl2-(5-bromo-4-((R)-3-(tert-butoxycarbonylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamoyl)morpholine-4-carboxylatediastereomer #2 (80 mg, 0.13 mmol) in DCM (3 mL) at room temperature wastreated with TFA (1 mL). The mixture was stirred at room temperature for1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase HPLC (0-50% ACN in water). The productisolated was next dissolved in minimal DCM (with MeOH to aid solubility)and added to a stirring solution of 1M HCl in ether. The resulting solidwas filtered, washed with ether and dried to giveN-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)morpholine-2-carboxamidehydrochloride diastereomer #2 (44 mg, 64% yield). ¹H NMR (400 MHz, D₂O)δ 8.18 (s, 1H), 7.57 (s, 1H), 4.55-4.51 (m, 1H), 4.20-4.16 (m, 1H),3.97-3.90 (m, 1H), 3.67-3.64 (m, 1H), 3.49-3.29 (m, 5H), 3.20-3.08 (m,2H), 2.95-2.92 (m, 1H), 2.09-2.06 (m, 1H), 1.81-1.69 (m, 21H), 1.53-1.49(m, 1H); LCMS (APCI+) m/z 423, 425 (M+H)+.

Example 73

(N-(4-(3-Amino-3-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg,0.298 mmol), tert-butyl 3-methylpiperidin-3-ylcarbamate (192 mg, 0.895mmol) and DIEA (0.052 mL, 0.298 mmol) in n-BuOH (3 mL) were stirred at143° C. (bath) for 24 hours. The solvent was removed, and the residuewas dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine(10 mL), dried (sodium sulfate), and concentrated in vacuo. The residueobtained was purified by C-18 reverse phase flash chromatography(Biotage SP4 unit, C-18 25M+ column, 10-80% CH₃CN/water gradient; 30CV). The product isolated was dissolved in DCM (2 mL), and TFA (0.5 mL)was added. The mixture was stirred at room temperature for 1 hour. Thesolvent was then removed. The residue was dissolved in DCM (1 mL), and2N HCl in ether (3 mL) was added. The solid formed was collected byfiltration to giveN-(4-(3-amino-3-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (12.8 mg, 7.96% yield) as a solid. ¹H NMR (400 MHz,(CD₃)₂SO) δ 12.09 (s, 1H), 10.54 (s, 1H), 9.37 (s, 1H), 8.91 (d, 1H),8.70 (m, 1H), 8.29 (s, 1H), 8.05 (s, 3H), 7.83 (m, 1H), 7.54 (s, 1H),3.40 (m, 2H), 3.27 (m, 1H), 3.17 (m, 2H), 1.65 (m, 2H), 1.46 (m, 1H),2.00 (s, 3H); LCMS (APCI+) m/z 429 (M+H)+.

Example 74

N-(4-(3-Amino-3-methylpiperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

A mixture of N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide(50 mg, 0.18 mmol; Example 13, Step D), tert-butyl3-methylpiperidin-3-ylcarbamate (78 mg, 0.37 mmol, Example C) and DIEA(0.032 mL, 0.182 mmol) in n-BuOH (1 mL) was stirred at 150° C. (bath)for 24 hours in a sealed tube. The solvent was removed, and theresulting residue was dissolved in ethyl acetate (20 mL), washed withwater (10 mL), brine (10 mL), dried (sodium sulfate) and concentrated invacuo. The residue obtained was purified by C-18 reverse phase flashchromatography (Biotage SP4 unit, C-18 25M column, 10-80% CH₃CN/watergradient; 30 CV). The product isolated was dissolved in DCM (2 mL), andTFA (0.5 mL) was added. The mixture was stirred at room temperature for1 hour. The solvent was removed. The residue was dissolved in MeOH (1mL), and 2N HCl in ether (3 mL) was added. The solid formed wascollected by filtration to giveN-(4-(3-amino-3-methylpiperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (0.050 g, 56%) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ12.04 (s, 1H), 11.03 (s, 1H), 9.49 (s, 1H), 8.95 (m, 2H), 8.27 (s, 2H),8.18 (d, 1H), 7.93 (m, 1H), 7.53 (d, 1H), 3.43 (m, 1H), 3.36 (m, 2H),3.04 (m, 1H), 1.71 (m, 1H), 1.51 (m, 2H), 1.31 (m, 1H), 1.22 (s, 3H).LCMS (APCI+) m/z 369 (M+H)+.

Example 75

(R)—N-4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (750 mg, 3.26mmol; Example 1, Step H), TEA (1.4 mL, 9.78 mmol), and Ac₂O (0.7 mL,6.85 mmol) were placed in THF (15 mL) and stirred for 30 minutes. Thereaction mixture was filtered, and the solid was dried to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (595 mg, 67%yield), which was used without further purification.

Step B: N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (400mg, 1.47 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (1.0 g, 5.15mmol) were placed in n-butanol (4 mL) and heated to 155° C. in a sealedtube for 18 hours. The reaction was then cooled and concentrated. Theresulting residue was purified by C-18 reverse phase flashchromatography (Biotage Horizon unit, C-18 25M column, 5-85%CH₃CN/water) to give (R)-tert-butyl1-(3-acetamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(543 mg, 77% yield).

Step C: (R)-tert-Butyl1-(3-acetamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(70 mg, 0.15 mmol) was placed in TFA (2 mL) and stirred for 30 minutes.The reaction was then concentrated, and the residue was purified by C-18reverse phase flash chromatography (Biotage Horizon unit, C-18 12Mcolumn, 0-45% CH₃CN/water with 0.1% TFA). The product was then dissolvedin 10% MeOH in DCM (2 mL) and added dropwise to a stirred solution of 2MHCl in ether. The precipitate was filtered and dried to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamidehydrochloride (15 mg, 23% yield). ¹H NMR (400 MHz, D₂O) δ 8.21 (s, 1H),7.26 (s, 1H), 3.58 (d, 1H), 3.49 (s, 1H), 3.25-3.10 (m, 3H), 2.11 (s,3H), 2.05 (m, 1H), 1.80 (m, 1H), 1.69-1.50 (m, 2H). LCMS (APCI+) m/z351.9 (M+H)+, Retention time=1.87 minutes (Method 3).

Example 76

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methoxycyclopropanecarboxamide

Step A: NaH (738 mg, 18.44 mmol; 60% dispersion in oil) was added to asolution of methyl 1-hydroxycyclopropanecarboxylate (1.83 g, 14.18 mmol)in anhydrous THF (15 mL) cooled on an ice bath. The mixture was stirredfor 15 minutes then iodomethane (3.22 g, 1.42 mL, 22.69 mmol) was addedslowly, and the resulting mixture stirred at ambient temperature for 18hours. The reaction mixture was quenched with ammonium chloride andextracted with EtOAc (3×20 mL). The combined organic extracts werewashed with water, dried over MgSO₄, and filtered. The filtrate wasevaporated under reduced pressure to give methyl1-methoxycyclopropanecarboxylate. An aqueous 6N NaOH solution (4 mL) wasadded to a solution of methyl 1-methoxycyclopropanecarboxylate (1.08 g,8.3 mmol) in anhydrous THF (5 mL). The mixture was stirred at roomtemperature for 18 hours, then acidified with aqueous 6N HCl andextracted with EtOAc (3×15 mL). The combined organic layer was driedover MgSO₄, filtered and concentrated to give1-methoxycyclopropanecarboxylic acid (892 mg, 54% yield) as an oil. ¹HNMR (400 MHz, (CD₃)₂SO) δ 12.40 (br s, 1H), 3.30 (s, 3H), 1.15-1.10 (m,2H), 1.08-1.04 (m, 2H).

Step B: Triethylamine (550 mg, 0.757 mL, 5.43 mmol) was slowly added toa mixture of 5-bromo-4-fluoro-1H-indol-3-amine (250 mg, 1.087 mmol,Example 1, step H), 1-methylcyclopropanecarboxylic acid (151 mg, 1.30mmol) and bis(2-oxooxazolidin-3-yl)phosphinic chloride (415 mg, 1.63mmol) in anhydrous dichloromethane (10 mL). The resulting solution wasstirred at room temperature for 3 hours. The mixture was concentrated,and the residue purified by reverse phase chromatography (Biotage SP4C-18 25M column, 10-75% CH₃CN/water, 25CV) to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methoxycyclopropanecarboxamide(216.5 mg, 60%) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.04 (br s,1H), 9.57 (s, 1H), 8.36 (d, 1H), 7.54 (d, 1H), 3.39 (s, 3H), 1.16-1.11(m, 4H). LCMS (APCI+) m/z 327.9 (M+H)+, Retention time=2.96 minutes.

Step C: (R)-tert-Butyl piperidin-3-ylcarbamate (366 mg, 1.83 mmol) wasadded to a suspension ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methoxycyclopropanecarboxamide(200 mg, 0.61 mmol) in n-BuOH (3 mL). The resulting mixture was heatedin a sealed tube at 160° C. for 24 hours. The cooled mixture was dilutedwith water (40 mL) and extracted with EtOAc (3×20 mL). The combinedorganic layers were dried over MgSO₄ and filtered, and the filtrate wasconcentrated. The residue was purified by reverse phase chromatography(Biotage SP4, C-18 25M+, 15-85% CH₃CN/water, 25CV) to give(R)-tert-butyl1-(5-bromo-3-(1-methoxycyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(103 mg, 33% yield) as a solid. LCMS (APCI+) m/z 510 (M+2H)+, Retentiontime=3.84 minutes.

Step D: (R)-tert-Butyl1-(5-bromo-3-(I-methoxycyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(103 mg, 0.203 mmol) was stirred in trifluoroacetic acid (3 mL) at roomtemperature for 1.5 hours. The solvent was evaporated in vacuo, and theresidue was purified by reverse phase chromatography (Biotage SP4, C-1812M+, 1-50% CH₃CN/water, 16CV). The isolated product was taken up in aminimal volume of methanol and added to a stirred solution of 2NHCl-Et₂O. The salt formed was collected by filtration, washed withacetonitrile and dried under vacuum to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methoxycyclopropanecarboxamidehydrochloride (28 mg, 28% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.30 (s, 1H), 7.36 (s, 1H), 3.75-3.67 (m, 1H), 3.60-3.49 (m, 1H),3.39-3.33 (m, 3H), 3.30-3.13 (m, 3H), 2.12-2.03 (m, 1H), 1.85-1.76 (m,1H), 1.74-1.62 (m, 1H), 1.60-1.49 (m, 1H), 1.31-1.13 (m, 4H). LCMS(APCI+) m/z 408, 410 (M+H)+, Retention time=2.14 minutes.

Example 77

(R)—N-(5-Bromo-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

Step A: Triethylamine (0.757 mL, 5.43 mmol) was added dropwise to amixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (250 mg,1.087 mmol; Example 1, Step H) and isobutyl chloride (139 mg, 0.137 mL,1.30 mmol) in dry dichloromethane (10 mL) cooled on an ice-bath, and thesolution was stirred at room temperature for 3 hours. The mixture wasconcentrated. The residue was stirred in THF (10 mL), treated with anaqueous 2N LiOH solution (3 mL), and the resulting mixture was stirredat room temperature for 1 hour. The organic solvent was evaporated invacuo, and the residue was stirred in water (20 mL). The solid, whichseparated, was collected by filtration, washed with water anddichloromethane (10 mL), and dried toN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (228.5mg, 70% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.04 (br s,1H), 9.41 (s, 1H), 8.34 (d, 1H), 7.56 (s, 1H), 2.72-2.60 (m, 1H), 1.11(d, 6H). LCMS (APCI+) m/z 299.9 (M+H)+, Retention time=2.80 minutes.

Step B: (R)-tert-Butyl methyl(piperidin-3-yl)carbamate (471 mg, 2.20mmol; Example E) was added to a suspension ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (220 mg,0.733 mmol) in n-BuOH (2.5 mL). The resulting mixture was heated in asealed tube at 160° C. for 24 hours. The cooled mixture was diluted withwater (40 mL) and extracted with EtOAc (3×20 mL). The combined organiclayer was dried over MgSO₄, filtered and concentrated. The residue waspurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-90%CH₃CN/water, 25CV) to give (R)-tert-butyl1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(48 mg, 13% yield) as a solid. LCMS (APCI+) m/z 494.1, 497.1 (M+H)+,Retention time=4.18 minutes.

Step C: (R)-tert-Butyl1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(65 mg, 0.12 mmol) was stirred in trifluoroacetic acid (3 mL) at roomtemperature for 1.5 hours. The solvent was evaporated in vacuo, and theresidue was purified by reverse phase chromatography (Biotage SP4, C-1812M+, 2-50% CH₃CN/water, 16CV). The isolated product was taken up in aminimal volume of methanol and added to a stirred solution of 2NHCl-Et₂O. The salt formed was collected by filtration, washed withacetonitrile and dried under vacuum to give(R)—N-(5-bromo-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (29 mg, 64% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.81 (br s, 1H), 9.23 (s, 2H), 8.25 (s, 1H), 7.60 (s, 1H), 3.60-3.45(m, 2H), 3.35-3.20 (m, 2H), 3.15-3.05 (m, 1H), 2.74-2.63 (m, 1H), 2.57(t, 3H), 2.32-2.20 (m, 1H), 1.95-1.84 (m, 1H), 1.74-1.60 (m, 1H),1.58-1.43 (m, 1H), 1.16 (d, 6H). LCMS (APCI+) m/z 396.1, 397.1 (M+2H)+,Retention time=2.13 minutes.

Example 78

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-2-methylpropanamide

Step A: 1-Chloro-2-methyl-1-oxopropan-2-yl acetate (215 mg, 1.30 mmol)in dry dichloromethane (2 mL) was added dropwise to a solution of5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (250 mg, 1.087 mmol;Example 1, Step H) and triethylamine (550 mg, 0.757 mL, 5.43 mmol) indry dichloromethane (10 mL) cooled on an ice-bath. The resultingsolution was stirred at room temperature for 1 hour. The solvent wasevaporated. The residue was then stirred in THF (10 mL), treated with anaqueous 2N LiOH solution (3 mL), and stirred at room temperature for 18hours. The mixture was evaporated under reduced pressure, and theresidue dissolved in EtOAc and washed with water (3×20 mL). The organiclayer was dried over MgSO₄, filtered and concentrated to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-2-methylpropanamide(289 mg, 84% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.03 (brs, 1H), 9.27 (s, 1H), 8.36 (d, 1H), 7.69 (d, 1H), 5.84 (s, 1H), 1.37 (s,6H); LCMS (APCI+) m/z 317.9 (M+H)+, Retention time=2.51 minutes.

Step B: (R)-tert-Butyl piperidin-3-ylcarbamate (538 mg, 2.69 mmol) andN,N-diisopropylethylamine (347 mg, 0.468 mL, 2.69 mmol) were added to asuspension ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-2-methylpropanamide(283 mg, 0.895 mmol) in n-BuOH (3 mL). The resulting mixture was heatedat 150° C. in a sealed tube for 24 hours. The cooled mixture was dilutedwith water and extracted with EtOAc (3×20 mL). The combined organiclayers were dried over MgSO₄ and filtered, and the filtrate concentratedto an oil and purified by reverse phase chromatography (Biotage SP4,C-18 25M+, 15-75% CH₃CN/water, 25CV) to give (R)-tert-butyl1-(5-bromo-3-(2-hydroxy-2-methylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(242 mg, 55% yield) as a solid. LCMS (APCI+) m/z 496.2, 498.2 (M+H)+,Retention time=3.53 minutes.

Step C: (R)-tert-Butyl1-(5-bromo-3-(2-hydroxy-2-methylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(242 mg, 0.488 mmol) was stirred at room temperature in trifluoroaceticacid (3 mL) for 1.5 hours. The TFA was evaporated in vacuo, and theresidue was purified by reverse phase chromatography (Biotage SP4, C-1812M+, 2-55% CH₃CN/water, 16CV). The isolated product was taken up in aminimal volume of methanol and added to a stirred solution of 2NHCl-Et₂O. The salt formed was collected by filtration, washed withacetonitrile and dried under vacuum to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-2-methylpropanamidehydrochloride (200 mg, 87% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.71 (br s, 1H), 10.23 (s, 1H), 8.32 (br s, 2H), 8.25 (s, 1H), 7.96(d, 1H), 3.69-3.48 (m, 3H), 3.34-3.23 (m, 1H), 3.05-2.92 (m, 1H),2.14-2.05 (m, 2H), 1.86-1.75 (m, 1H), 1.55-1.43 (m, 1H), 1.39 (d, 6H);LCMS (APCI+) m/z 396, 398 (M+H)+, Retention time=2.14 minutes.

Example 79

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: Phenylboronic acid (28.4 mg, 0.233 mmol), PS-palladium tetrakis(88.2 mg, 0.00970 mmol, 0.10 mmol/1 g) and 2N sodium carbonate (194 i±L,0.388 mmol) were added to (R)-tert-butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(100 mg, 0.194 mmol; Example 1A, Step 1) in degassed dioxane (1 mL). Thereaction was heated to 150° C. for 1 hour under microwave irradiation.Phenylboronic acid (28.4 mg, 0.233 mmol) and 2N sodium carbonate (194μL, 0.388 mmol) were added, and the reaction was heated to 150° C. foran additional 2 hours under microwave irradiation and then cooled downand filtered. The filtrate was diluted with DCM, dried with MgSO₄,filtered, and concentrated. The resulting residue was purified byreverse phase chromatography (Biotage Horizon, C-18 25M+, 10-90%CH₃CN/water) to yield (R)-tert-butyl1-(3-(nicotinamido)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(60 mg, 60% yield) as a solid.

Step B: (R)-tert-Butyl1-(3-(nicotinamido)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(60 mg, 0.12 mmol) in TFA (2 mL) was stirred for 30 minutes. Thereaction was concentrated, and the residue was purified by C-18 reversephase flash chromatography (Biotage Horizon unit, C-18 12S column, 0-45%CH₃CN/water with 0.1% TFA). The resulting solid was dissolved in 10%MeOH in DCM (2 mL) and added dropwise to a stirring solution of 2M HClin ether. Concentration yielded(R)—N-(4-(3-aminopiperidin-1-yl)-5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride as a solid (24 mg, 39% yield). ¹H NMR (400 MHz, D₂O) δ9.14 (s, 1H), 8.81 (s, 1H), 8.71 (d, 1H), 7.91 (m, 2H), 7.50-7.31 (m,6H), 3.56 (m, 1H), 3.26 (m, 1H), 2.89 (m, 1H), 2.45 (m, 2H), 1.69 (m,1H), 1.36 (m, 1H), 1.25-1.00 (m, 2H). LCMS (APCI+) m/z 413.1 (M+H)+,Retention time=2.25 minutes (Method 3).

Example 80

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamide

Step A: di-tert-Butyl dicarbonate (422 mg, 1.93 mmol), triethylamine(674 μL, 4.83 mmol), and N,N-dimethylpyridin-4-amine (98.4 mg, 0.806mmol) was added to a solution of (R)-tert-butyl1-(5-bromo-3-(3-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(800 mg, 1.61 mmol; Example 54, Step B) in CH₂Cl₂ (15 mL). The mixturewas then stirred at room temperature. After 18 hours, additionaldi-tert-butyl dicarbonate (422 mg, 1.93 mmol) and triethylamine (674 μL,4.83 mmol) were added, and the mixture was stirred at room temperaturefor 5 hours. The mixture was then poured into water, and the layers wereseparated. The aqueous phase was extracted with CH₂Cl₂ (2×30 mL), andthe combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo. The crude was purified by flash chromatography onsilica gel (Biotage Flash 40S+, 40% EtOAc/hexane) to provide the(R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(3-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(378 mg, 39% yield) as a solid. LCMS (APCI+) m/z 596.2, 598 (M+H)+.

Step B: A mixture of (R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(3-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(370 mg, 0.620 mmol), cyclopropylboronic acid (213 mg, 2.48 mmol),tricyclohexylphosphine (20.9 mg, 0.0744 mmol), K₃PO₄ (461 mg, 2.17mmol), and diacetoxypalladium (13.9 mg, 0.0620 mmol) in toluene/water(10:1 mixture, 9 mL) was stirred at 80° C. for 22 hours. The mixture wasthen diluted with EtOAc (60 mL) and water (10 mL) was added. The layerswere separated, and the aqueous layer was extracted with EtOAc (3×20mL). The combined organic layers were dried (MgSO₄), filtered, andconcentrated in vacuo. The oily residue was purified by reverse phasechromatography (Biotage SP4, C-18 25M+, 20%-90% CH₃CN/water, 24CV) toprovide (R)-tert-butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-cyclopropyl-3-(3-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(77 mg, 22% yield) as a solid. LCMS (APCI+) m/z 558 (M+H)+.

Step C: A solution of (R)-tert-butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-cyclopropyl-3-(3-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(70 mg, 0.13 mmol) in neat TFA was stirred at room temperature for 50minutes and concentrated in vacuo. The residue was dissolved in amixture of MeOH:CH₂C₂ (1:2, 1 mL) and 2M HCl in ether was added. Thesuspension formed was concentrated in vacuo and rinsed with CH₂Cl₂ (2×2mL) and triturated with CH₃CN (3 mL). The resulting solid was driedunder high vacuum to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methoxypropanamidehydrochloride (15 mg, 33% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 12.06 (s, 1H), 9.56 (s, 1H), 8.28 (br s, 3H), 7.94 (s, 1H), 7.41 (d,1H), 3.82-3.76 (m, 1H), 3.59 (t, 2H), 3.42-3.33 (m, 3H), 3.30-3.27 (m,1H), 3.22 (s, 3H), 2.60 (t, 2H), 2.10-2.05 (m, 1H), 2.01-1.97 (m, 1H),1.81-1.75 (m, 1H), 1.70-1.62 (m, 1H), 1.56-1.48 (m, 1H), 1.01-0.95 (m,2H), 0.75-0.69 (m, 2H). LCMS (APCI+) m/z 358.1 (M+H)+.

Example 81

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

Step A: (R)-tert-Butyl1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.300 g, 0.624 mmol; Example 15, Step B) was placed in DCM (8 mL).Boc₂O (0.150 g, 0.687 mmol) and triethylamine (0.261 mL, 1.87 mmol) werethen added, followed by the addition of DMAP (0.0381 g, 0.312 mmol). Thereaction was stirred for an additional 30 minutes, then poured intowater, and extracted with DCM. The combined organic fractions were dried(MgSO₄), filtered, and concentrated to give the crude product, which waspurified by chromatography (500:8 DCM:MeOH) to give (R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(0.33 g, 91% yield).

Step B: (R)-tert-Butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(0.340 g, 0.586 mmol), cyclopropylboronic acid (0.201 g, 2.34 mmol),K₂PO₄ (0.435 g, 2.05 mmol), Pd(OAc)₂ (0.0131 g, 0.0586 mmol), and P(Cy)₃(0.0197 g, 0.0703 mmol) were placed in 10:1 toluene:water (4.4 mL totalvolume) and degassed under argon and then heated to 80° C. for 18 hours.The reaction was then cooled to room temperature, poured into water andextracted with DCM. The organic fraction was dried, filtered, andconcentrated to give the crude product that was purified by reversephase chromatography (Biotage SP4, C-18 25M+, 5-95% CH₃CN/H₂O) to giveboth (R)-tert-butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-cyclopropyl-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(0.15 g, 47% yield) and a small amount of (R)-tert-butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(0.01 g, 3% yield).

Step C: (R)-tert-Butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-cyclopropyl-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(0.150 g, 0.277 mmol) was placed in DCM (5 mL). TFA (1 mL) was thenadded, and the reaction was stirred at room temperature for 1 hour andconcentrated to dryness. The resulting product was dissolved in minimalDCM (with MeOH to aid solubility) and added to a stirred solution of 1MHCl in ether. The resulting solid was filtered, washed with ether anddried to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (0.085 g, 74% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ7.88 (s, 1H), 7.25 (s, 1H), 3.96-3.93 (m, 1H) 3.53-3.49 (m, 1H)3.42-3.37 (m, 2H), 3.32-3.27 (m, 1H), 3.22-3.17 (m, 1H), 2.70-3.63 (m,11H), 2.14-2.12 (m, 1H), 1.89-1.86 (m, 1H), 1.80-1.77 (m, 1H), 1.69-1.66(m, 1H), 1.54-1.52 (m, 1H), 1.12-1.09 (m, 6H), 0.99-0.96 (m, 2H),0.66-0.62 (m, 2H); LCMS (APCI+) m/z 342 (M+H)+.

Example 82

(R)—N-(4-(3-Aminopiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

(R)-tert-Butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(0.010 g, 0.020 mmol; Example 81, Step B) was placed in DCM (3 mL) atroom temperature. TFA (1 mL) was then added, and the reaction wasstirred at room temperature for 1 hour and concentrated to dryness. Theresulting residue was then purified by reverse phase chromatography(Biotage SP4, C-18 12M+, 0-50% ACN in water). The resulting product wasnext dissolved in minimal DCM (with MeOH to aid solubility) and added toa stirred solution of 1M HCl in ether. The resulting solid was filtered,washed with ether and dried to give(R)—N-(4-(3-aminopiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (0.002 g, 27% yield). LCMS (APCI+) m/z 302 (M+H)+.

Example 83

N-(4-((R)-3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-difluorocyclopropanecarboxamide

Step A: A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(200 mg, 0.869 mmol; Example 1, Step H),2,2-difluorocyclopropanecarboxylic acid (212 mg, 1.74 mmol), andtriethylamine (606 μL, 4.35 mmol) in CH₂Cl₂ (5 mL) at room temperaturewas treated with BOP-Cl (162 mg, 1.74 mmol). The mixture was stirred atroom temperature for 18 hours. 2M LiOH.H₂O (3 mL) was then added to themixture and stirred for 30 minutes. Water (10 mL) was added, and theformed solid was filtered, washed with additional water (3×5 mL), anddried to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-difluorocyclopropanecarboxamide(158 mg, 54% yield) as a solid. LCMS (APCI+) m/z 334, 336 (M+H)+.

Step B: A sealed tube was charged withN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-difluorocyclopropanecarboxamide(150 mg, 0.449 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (270 mg,1.35 mmol), N-ethyl-N-isopropylpropan-2-amine (235 μL, 1.35 mmol) andn-BuOH (3 mL). Then N₂ was bubbled through the mixture for 5 minutes.The tube was sealed under N₂ and stirred at 120° C. for 5 hours and thenat 130° C. for 48 hours. The mixture was concentrated in vacuo, and theresidue was purified by reverse phase chromatography (Biotage SP4, C-1825M+, 15-85% CH₃CN/water, 23 CV) to yield tert-butyl(3R)-1-(5-bromo-3-(2,2-difluorocyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(81 mg, 35% yield) as a solid. LCMS (APCI+) m/z 514.1, 516.1 (M+H)+.

Step C: A solution of tert-butyl(3R)-1-(5-bromo-3-(2,2-difluorocyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(80 mg, 0.16 mmol) in neat TFA (2 mL) was stirred at room temperaturefor 30 minutes and concentrated in vacuo. The residue was purified byreverse phase chromatography (Biotage SP4, C-18 12M+, 0-40% CH₃CN/water,14 CV). The residue was dissolved in MeOH (1 mL) and added dropwise to a2N HCl in ether solution. The resulting solid was filtered and dried toyieldN-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-difluorocyclopropanecarboxamidehydrochloride (15 mg, 20% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.91 (d, 1H), 9.87 (br s, 1H), 8.25 (br s, 3H), 8.23 (s, 1H), 7.52(s, 1H), 3.49-3.42 (m, 3H), 3.21-3.15 (m, 1H), 3.09-3.02 (m, 2H),2.12-2.09 (m, 1H), 2.05-1.98 (m, 2H), 1.83-1.75 (m, 2H), 1.54-1.44 (m,1H). LCMS (APCI+) m/z 414, 416 (M+H)+.

Example 84

(R)—N-(4-(3-Aminopiperidin-1-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

(R)-tert-Butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(125 mg, 0.243 mmol; Example 1A, Step A) was dissolved in dioxane (20mL) and cooled to −78° C. MeLi (455 μL, 0.728 mmol) was slowly added,and the reaction was stirred for 10 minutes. n-Butyl lithium (146 μL,0.364 mmol) was slowly added, and the reaction was stirred for 10minutes at −78° C. Saturated ammonium chloride was then added, and themixture was extracted several times with DCM. The layers were separated,dried, filtered, and concentrated. The residue was purified by reversephase chromatography (Biotage Horizon, C-18 25M+, 0-80% CH₃CN/water+10mM ammonium acetate and 1% IPA). The product was dissolved in TFA (2mL), stirred for 30 minutes, concentrated and purified by reverse phasechromatography (Biotage Horizon, C-18 12M+, 0-30% CH₃CN/water+0.1% TFA).The product was redissolved in 10% MeOH in DCM (2 mL) and added dropwiseto a stirred solution of 2M HCl in ether. The reaction was concentratedto give(R)—N-(4-(3-aminopiperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (18.5 mg, 17% yield). ¹H NMR (400 MHz, D₂O) δ 9.10 (s,1H), 8.78 (d, 1H), 8.62 (dt, 1H), 7.94 (d, 1H), 7.85 (dd, 1H), 7.39 (s,1H), 6.78 (d, 1H), 3.89 (d, 1H), 3.72 (d, 1H), 3.33 (m, 1H), 3.21-3.09(m, 2H), 1.93 (m, 1H), 1.58 (m, 1H), 1.47 (m, 1H), 1.36 (m, 1H). LCMS(APCI+) m/z 337.1 (M+H)+, Retention time=0.43 minutes (Method 3).

Example 85

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-(methylthio)-1H-pyrrolo[2,3-b]pyridin-3-ylnicotinamide

Step A: (R)-tert-Butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(150 mg, 0.291 mmol; Example 1A, Step A) was dissolved in THF (20 mL)and cooled to −78° C. MeLi (546 μL, 0.873 mmol) was then added slowly,and the reaction was stirred for 10 minutes. n-Butyl lithium (128 μL,0.320 mmol) was added next, and the reaction was stirred for anadditional 10 minutes, followed by the addition of 1,2-dimethyldisulfane(31.5 mg, 0.335 mmol). The reaction was stirred for 30 minutes and thenquenched with water. The reaction was extracted several times with DCM.The organic layer was dried, filtered, and concentrated. The resultingresidue was purified by reverse phase chromatography (Biotage Horizon,C-18 25M+, 10-85% CH₃CN/water) to provide 50% pure (R)-tert-butyl1-(5-(methylthio)-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate,which was used without further purification.

Step B: (R)-tert-Butyl1-(5-(methylthio)-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(80 mg, 0.16 mmol) was placed in TFA (2 mL) and stirred for 15 minutes.The reaction was then concentrated and dissolved in 10% MeOH in DCM andthen washed with saturated sodium bicarbonate. The organic layer wasdried, filtered, and concentrated. The residue was purified by reversephase prep LC. The product was then dissolved in 10% MeOH in DCM andadded to a stirred solution of 2M HCl in ether. The reaction mixture wasconcentrated to provided(R)—N-(4-(3-aminopiperidin-1-yl)-5-(methylthio)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (18.7 mg, 17% yield). ¹H NMR (400 MHz, D₂O) δ 9.10 (s,1H), 8.78 (d, 1H), 8.61 (dt, 1H), 8.16 (s, 1H), 7.84 (dd, 1H), 7.42 (s,1H), 3.88 (d, 1H), 3.56 (m, 1H), 3.47 (m, 1H), 3.14 (m, 1H), 3.04 (m,1H), 2.36 (s, 3H), 1.94 (m, 1H), 1.67 (m, 1H), 1.55 (m, 1H), 1.37 (m,1H). LCMS (APCI+) m/z 383.1 (M+H)+, Retention time=1.99 minutes (Method3).

Example 86

(R)—N-(5-Bromo-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide

Step A: A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide(0.26 g, 0.72 mmol; Example 23, Step A), (R)-tert-butylmethyl(piperidin-3-yl)carbamate (0.46 g, 2.15 mmol) and DIEA (0.38 mL,2.15 mmol) in n-BuOH (2 mL) was stirred at 143° C. (bath) for 24 hours.The solvent was removed, and the residue was dissolved in THF (2 mL).Boc₂O (0.39 g, 1.79 mmol) was added. The reaction mixture was stirred atroom temperature for 3 hours. Ethyl acetate (20 mL) was added, washedwith water (10 mL), brine (10 mL), dried (sodium sulfate) andconcentrated in vacuo. The residue was purified by reverse phasechromatography (Biotage SP4, C-18 25M+, 10-90% CH₃CN/water, 30 CV) togive (R)-tert-butyl 5-bromo-4-(3-(tert-butoxycarbonyl(methyl)amino)piperidin-1-yl)-3-(1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(0.072 g, 15%) as a solid. LCMS (APCI+) m/z 659 (M+H)+.

Step B: TFA (0.020 mL, 0.26 mmol) was added to (R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonyl(methyl)amino)piperidin-1-yl)-3-(1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(0.034 g, 0.052 mmol) in DCM (1 mL). The reaction mixture was stirred atroom temperature for 1 hour. The solvent was removed. The residue wasdissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solidformed was collected to give(R)—N-(5-bromo-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamidehydrochloride (25 mg, 91%) as a solid. ¹H NMR (400 MHz, D₂O) δ 8.34 (s,1H), 8.30 (s, 1H), 7.97 (dd, 1H), 7.35 (s, 1H), 6.60 (d, 1H), 3.88 (m,1H), 3.53 (s, 3H), 3.39 (m, 2H), 3.08 (m, 2H), 2.55 (s, 3H), 2.04 (m,1H), 1.68 (m, 1H), 1.60 (m, 1H), 1.35 (m, 1H). LCMS (APCI+) m/z 459(M+H)+.

Example 87

N-(4-(cis-3-amino-4-fluoropiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (0.11 g,0.37 mmol; Example 15, Step A),benzyl-cis-4-fluoropiperidin-3-ylcarbamate (0.19 g, 0.75 mmol; ExampleF) and DIEA (0.26 mL, 1.49 mmol) in n-BuOH (2 mL) was stirred at 155° C.(bath) for 22 hours. The solvent was removed, and the residue wasdissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10mL), dried (sodium sulfate) and concentrated in vacuo. The residue waspurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 10-80%CH₃CN/water, 30 CV). The product isolated was dissolved in DCM (3 mL),and TMS-I (0.16 mL, 1.12 mmol) was added. The reaction mixture wasstirred at room temperature for 2 hours. The solvent was removed invacuo, water (10 mL) and ether (30 mL) were added. The aqueous layer wasseparated, basified with 30% potassium carbonate to a pH of about 9, andextracted with DCM (2×20 mL). The combined organic layers were dried(sodium sulfate) and concentrated in vacuo. The residue was dissolved inDCM (3 mL), and 2N HCl in ether (2 mL) was added. The solid formed wascollected to giveN-(4-(cis-3-amino-4-fluoropiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (36 mg, 21%) as a solid. ¹H NMR (400 MHz, D₂O) δ 8.25 (s,1H), 7.27 (s, 1H), 3.86 (m, 1H), 3.62 (m, 1H), 3.41 (m, 2H), 3.20 (m,1H), 2.64 (m, 1H), 2.12 (m, 2H), 1.96 (m 1H), 1.11 (t, 6H). LCMS (APCI+)m/z 398 (M+H)+.

Example 88

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide

Step A: (R)-tert-Butyl1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(883 mg, 1.71 mmol; Example 1A, Step A) was placed in DCM (8 mL). Boc₂O(411 mg, 1.88 mmol) and triethylamine (716 μL, 5.14 mmol) were thenadded, followed by the addition of DMAP (105 mg, 0.857 mmol). Thereaction was stirred at room temperature for 1 hour. The reaction wasthen poured into water and extracted with DCM. The combined organicfractions were dried (MgSO₄), filtered, and concentrated. The residuewas purified by silica gel chromatography (0-3% MeOH in DCM) to give(R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(903 mg, 85% yield).

Step B: (R)-tert-Butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(150 mg, 0.244 mmol), Zn(CN)₂ (19 mg, 0.158 mmol), Zn dust (4 mg, 0.0585mmol), Pd₂dba₃ (4.5 mg, 0.00487 mmol) and dppf (5.4 mg, 0.00975 mmol)were placed in DMA (5 mL) and heated at 90° C. for 24 hours. Thereaction was then poured onto water (20 mL) and extracted with ether.The organic layer was separated, washed with brine, and dried oversodium sulfate. After removal of solvent, the residue was purified byreverse phase chromatography (Biotage SP4, C-18 25M+, 5-95% water:ACN).The product was redissolved in 10% MeOH in DCM and added slowly to astirred solution of 2M HCl in ether (25 mL). The reaction wasconcentrated to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamidehydrochloride (24.8 mg, 22% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ9.21 (s, 1H), 8.89 (m, 2H), 8.31 (s, 1H), 8.08 (m, 1H), 7.42 (s, 1H),3.99 (d, 1H), 3.62 (d, 1H), 3.38 (m, 1H), 3.27 (m, 1H), 3.08 (m, 1H),1.95 (m, 1H), 1.62 (m, 1H), 1.43 (m, 2H). LCMS (APCI+) m/z 362.1 (M+H)+,Retention time=1.78 minutes (Method 3).

Example 89

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

Step A: (R)-tert-Butyl1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.300 g, 0.624 mmol; Example 15, Step B) was placed in THF (10 mL) andcooled to −78° C. MeLi (1.17 mL, 1.87 mmol) was then added, and thereaction was stirred for 10 minutes. Excess THF (10 mL) was added to aidsolubility. n-BuLi (0.525 mL, 1.31 mmol) was then added and stirred foran additional 10 minutes, followed by the addition of a hexachloroethane(0.296 g, 1.25 mmol) solution in THF (3 mL). The reaction was thenstirred for an additional 10 minutes at 0° C., poured into water, andextracted into DCM. The organic fractions were dried, filtered, andconcentrated to give a crude oil that was purified by reverse phase HPLC(50-75% ACN in water) to give the product (R)-tert-butyl1-(5-chloro-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.100 g, 36.7% yield).

Step B: (R)-tert-Butyl1-(5-chloro-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.100 g, 0.229 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added, and the reaction was stirred at room temperaturefor 1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase HPLC (0-50% ACN in water). The resultingproduct was next dissolved in minimal DCM (with MeOH to aid solubility)and added to a stirring solution of 1M HCl in ether. The resulting solidwas filtered, washed with ether and dried to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (0.050 g, 53.3% yield). ¹H NMR (400 MHz, D₂O) δ 8.11 (s,1H), 7.28 (s, 1H), 3.81-3.78 (m, 1H), 3.52-3.49 (m, 1H), 3.40-3.36 (m,1H), 3.20-3.15 (m, 2H), 2.66-2.63 (m, 1H), 2.09-2.06 (m, 1H), 1.78-1.77(m, 1H), 1.65-1.54 (m, 2H), 1.12-0.18 (m, 6H). LCMS (APCI+) m/z 336(M+H)+.

Example 90

N-(4-(Trans-3-amino-4-methoxypiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (0.18 g,0.58 mmol; Example 15, Step A), tert-butyltrans-4-methoxypiperidin-3-ylcarbamate (0.40 g, 1.75 mmol; Example G)and DIEA (0.31 mL, 1.75 mmol) in tert-amyl alcohol (3 mL) was stirred at146° C. (bath) for 22 hours. The solvent was removed. The resultingresidue was dissolved in ethyl acetate (20 mL), washed with water (10mL), brine (10 mL), dried (sodium sulfate) and concentrated in vacuo.The residue was purified by reverse phase chromatography (Biotage SP4,C-18 25M+, 10-80% CH₃CN/water, 30 CV). The isolated product wasdissolved in DCM (2 mL), and TFA (0.5 mL) was added. The mixture wasstirred at room temperature for 1 hour. The solvent was removed. Theresidue was dissolved in MeOH (1 mL), and 2N HCl in ether (3 mL) wasadded. The solid formed was collected to giveN-(4-((trans-3-amino-4-methoxypiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (0.065 g, 23%) as a solid. ¹H NMR (400 MHz, D₂O) δ 8.22(s, 1H), 7.29 (s, 1H), 3.74 (m, 1H), 3.39 (m, 3H), 3.32 (s, 3H), 3.25(m, 2H), 2.63 (m, 1H), 2.25 (m, 1H), 1.51 (m, 1H), 1.11 (t, 6H). LCMS(APCI+) m/z 411 (M+H)+.

Example 90A

N-(4-((3R,4R)-3-amino-4-methoxypiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

Chiral separation of Example 90: Chiral OD-H (20 mm×250 mm); 70% hexane,30% 1:1 ethanol:methanol; flow rate 15 mL/min. ¹H NMR (400 MHz, D₂O) δ8.23 (s, 1H), 7.29 (s, 1H), 3.80 (m, 1H), 3.41 (m, 3H), 3.32 (s, 3H),3.23 (m, 2H), 2.64 (m, 1H), 2.25 (m, 1H), 1.51 (m, 1H), 1.11 (t, 6H).LCMS (APCI+) m/z 410 (M+H)+. Enantiomeric excess determined by chiralHPLC (Chiral OD-H (4.6 mm×250 mm); 70% hexane, 30% 1:1 ethanol:methanol;flow rate 0.8 mL/min), 96.2% ee.

Example 90B

N-(4-((3S,4S)-3-amino-4-methoxypiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

Chiral separation of Example 90: Chiral OD-H (20 mm×250 mm); 70% hexane,30% 1:1 ethanol:methanol; flow rate 15 mL/min. ¹H NMR (400 MHz, D₂O) δ8.22 (s, 1H), 7.28 (s, 1H), 3.74 (m, 1H), 3.40 (m, 3H), 3.32 (s, 3H),3.24 (m, 2H), 2.63 (m, 1H), 1.90 (m, 1H), 1.50 (m, 1H), 1.11 (t, 6H).LCMS (APCI+) m/z 410 (M+H)+. Enantiomeric excess determined by chiralHPLC (Chiral OD-H (4.6 mm×250 mm); 70% hexane, 30% 1:1 ethanol:methanol;flow rate 0.8 mL/min), 100% ee.

Example 91

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamide

Step A: A 250 mL round bottom flask was charged with5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (1.6 g, 8.62 mmol;Example 8, Step D), (R)-tert-butyl piperidin-3-ylcarbamate (5.18 g, 25.9mmol), N-ethyl-N-isopropylpropan-2-amine (4.51 mL, 25.9 mmol), and NMP(15.5 mL). Then N₂ was bubbled through the mixture for 5 minutes andstirred at 120° C. under N₂ atmosphere for 16 hours to provide the crude(R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate.LCMS (APCI+) m/z 366.1 (M+H)+.

Step B: Triethylamine (522 μL, 3.83 mmol) was added to an aliquot of(R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(200 mg, 0.547 mmol) in NMP (3 mL) at 0° C. under N₂ atmosphere. Themixture was then treated dropwise with 3-methylbutanoyl chloride (231mg, 1.91 mmol) and stirred at 0° C. After 1 hour, the reaction mixturewas diluted with CH₂Cl₂ (4 mL), and 2M LiOH.H₂O (3 mL) was added. Theresulting mixture was stirred at room temperature for 18 hours. Themixture was then diluted with additional CH₂Cl₂ (50 mL) and washed withwater (3×10 mL). The organic layer was separated, dried (MgSO₄),filtered, and concentrated in vacuo. The residue was purified by reversephase chromatography (Biotage SP4, C-18 40M+, 15-85% CH₃CN/water, 40 CV)to provide (R)-tert-butyl1-(5-chloro-3-(3-methylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(130 mg, 53% yield) as a solid.

Step C: A solution of (R)-tert-butyl1-(5-chloro-3-(3-methylbutanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(128 mg, 0.284 mmol) in neat TFA (3 mL) was stirred at room temperaturefor 30 minutes and concentrated in vacuo. The oily residue wasevaporated from CH₃CN (4×10 mL) to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methylbutanamidehydrochloride (95 mg, 79% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.77 (s, 1H), 9.26 (s, 1H), 8.22 (br s, 3H), 8.12 (s, 1H), 7.58 (brs, 1H), 3.47-3.31 (m, 3H), 3.25-3.17 (m, 1H), 3.13-3.08 (m, 1H), 2.25(d, 2H), 2.14-2.09 (m, 2H), 1.87-1.81 (m, 1H), 1.74-1.63 (m, 1H),1.54-1.47 (m, 1H), 0.98 (dd, 6H). LCMS (APCI+) m/z 350 (M+H)+.

Example 92

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

Step A: Triethylamine (1018 μL, 7.462 mmol) was added to an aliquot of(R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(390 mg, 1.066 mmol; Example 91, Step A) in NMP (3 mL) at 0° C. under N₂atmosphere. The mixture was treated dropwise with cyclopropanecarbonylchloride (580.4 μL, 6.396 mmol) and stirred at 0° C. for 1 hour. Thereaction mixture was then diluted with CH₂Cl₂ (4 mL). 2M LiOH.H₂O (9 mL)was added, and the mixture was allowed to stir for 24 hours. The mixturewas then diluted with 2% MeOH/EtOAc (100 mL) and washed with water (4×20mL). The organic layer was separated, dried (MgSO₄), filtered, andconcentrated in vacuo. The residue obtained was purified by reversephase chromatography (Biotage SP4, C-18 40M+, 15-85% CH₃CN/water, 38 CV)to provide (R)-tert-butyl1-(5-chloro-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamateas a solid.

Step B: A solution of (R)-tert-butyl1-(5-chloro-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(462 mg, 1.06 mmol) in neat TFA (4 mL) was stirred at room temperaturefor 30 minutes and concentrated in vacuo. The oily residue obtained wasdissolved in CH₂Cl₂ (1 mL) and treated with 2M HCl in ether (4 mL). Theresulting precipitate was evaporated from CH₃CN (4×10 mL) to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (271 mg, 63% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.79 (d, 1H), 9.65 (s, 1H), 8.25 (br s, 3H), 8.11 (s, 1H), 7.48 (d,1H), 3.53-3.48 (m, 1H), 3.44-3.31 (m, 2H), 3.23-3.11 (m, 2H), 2.13-2.08(m, 1H), 1.89-1.80 (m, 2H), 1.75-1.70 (m, 1H), 1.54-1.45 (m, 1H0, 0.82(d, 4H). LCMS (APCI+) m/z 334 (M+H)+.

Example 93

N-(4-(Trans-3-amino-4-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (0.20 g,0.67 mmol; Example 15, Step A), tert-butyltrans-4-methylpiperidin-3-ylcarbamate (0.43 g, 2.00 mmol; Example I) andDIEA (0.35 mL, 2.00 mmol) in n-BuOH (3 mL) was stirred at 146° C. (bath)for 24 hours. The solvent was removed, and the residue was dissolved inethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried(sodium sulfate) and concentrated in vacuo. The residue was purified byreverse phase chromatography (Biotage SP4, C-18 25M+, 10-80%CH₃CN/water, 30 CV). The product isolated was dissolved in DCM (2 mL),and TFA (0.5 mL) was added. The mixture was stirred at room temperaturefor 1 hour. The solvent was removed in vacuo. The residue was purifiedby reverse phase chromatography (Biotage SP4, C-18 12M+, 0-80%CH₃CN/water gradient, 20 CV). The product isolated was dissolved in MeOH(1 mL), and 2N HCl in ether (3 mL) was added. The solid formed wascollected to giveN-(4-(trans-3-amino-4-methylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (0.011 g, 4%) as a solid. ¹H NMR (400 MHz, D₂O) δ 8.20 (s,1H), 7.27 (s, 1H), 3.72 (m, 1H), 3.26 (m, 1H), 3.19 (m, 3H), 2.63 (m,1H), 1.76 (m, 1H), 1.68 (m, 1H), 1.41 (m, 1H), 1.10 (t, 6H), 1.00 (d,3H). LCMS (APCI+) m/z 394 (M+H)+.

Example 94

N-(4-(Trans-3-amino-4-fluoropiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylisobutyramide

A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (0.10 g,0.33 mmol; Example 15, Step A), tert-butyltrans-4-fluoropiperidin-3-ylcarbamate (0.22 g, 1.00 mmol, Example J) andDIEA (0.17 mL, 1.00 mmol) in n-BuOH (3 mL) was stirred at 146° C. (bath)for 40 hours. The solvent was removed, and the residue was dissolved inethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), dried(sodium sulfate) and concentrated in vacuo. The residue was purified byreverse phase chromatography (Biotage SP4, C-18 25M+, 10-80%CH₃CN/water, 20 CV). The product isolated was dissolved in DCM (2 mL),and TFA (0.5 mL) was added. The mixture was stirred at room temperaturefor 1 hour. The solvent was removed. The residue was dissolved in MeOH(1 mL), and 2N HCl in ether (3 mL) was added. The solid formed wascollected to giveN-(4-(trans-3-amino-4-fluoropiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (0.017 g, 11%) as a solid. ¹H NMR (400 MHz, D₂O) δ 8.24(s, 1H), 7.27 (s, 1H), 3.83 (m 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.25 (m,2H), 2.64 (m, 1H), 2.21 (m, 2H), 1.88 (m, 1H), 1.10 (m, 6H). LCMS(APCI+) m/z 398 (M+H)+.

Example 95

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxyacetamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.600 g, 2.61mmol; Example 1, Step H), 2-acetoxyacetic acid (0.647 g, 5.48 mmol),BOP-Cl (1.39 g, 5.48 mmol), and triethylamine (1.82 mL, 13.0 mmol) wereplaced in DCM (10 mL) and stirred at room temperature for 1 hour. 3Maqueous LiOH (3 mL) was then added. The reaction was stirred for 2hours, poured into water, and extracted with DCM. The combined organicfractions were dried (MgSO₄), filtered, and concentrated to give thecrude product, which was purified by reverse phase chromatography(Biotage SP4, C-18 25M+, 5-95 CH₃CN/water) to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxyacetamide(0.400 g, 53% yield).

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxyacetamide(0.200 g, 0.694 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (0.417 g,2.08 mmol), and DIEA (0.363 mL, 2.08 mmol) were placed in n-BuOH (2 mL)and heated to 140° C. for 18 hours. The reaction was then cooled to roomtemperature and concentrated to dryness. The resulting residue waspurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-75CH₃CN/water) to give (R)-tert-butyl1-(5-bromo-3-(2-hydroxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.220 g, 68% yield).

Step C: (R)-tert-Butyl1-(5-bromo-3-(2-hydroxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.220 g, 0.470 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added. The reaction was stirred at room temperature for1 hour and concentrated to dryness. The residue was purified by reversephase chromatography (Biotage SP4, C-18 25M+, 5-50 CH₃CN/water). Theresulting product was next dissolved in minimal DCM (with MeOH to aidsolubility) and added to a stirred solution of 1M HCl in ether. Theresulting solid was filtered, washed with ether and dried to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxyacetamidehydrochloride (0.045 g, 22% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.20 (s, 1H), 7.46 (s, 1H), 4.17 (s, 2H), 3.60-3.51 (m, 2H), 3.33-3.28(m, 1H), 3.22-3.13 (m, 2H), 2.08-2.05 (m, 1H), 1.76-1.72 (m, 2H),1.54-1.51 (m, 1H). LCMS (APCI+) m/z 368, 370 (M+H)+.

Example 96

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamide

Step A: An NMP (2 mL) solution of (R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.200 g, 0.547 mmol; Example 91, Step A), 2-methoxyacetyl chloride(0.302 mL, 3.28 mmol), and triethylamine (0.533 mL, 3.83 mmol) wasstirred at room temperature for 1 hour. 3M aqueous LiOH (3 mL) was thenadded. The reaction was stirred for 10 minutes, poured into water, andextracted with DCM. The combined organic fractions were dried (MgSO₄),filtered, and concentrated to give the crude product, which was purifiedby reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95CH₃CN/water) to give (R)-tert-butyl1-(5-chloro-3-(2-methoxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.185 g, 77% yield).

Step B: (R)-tert-Butyl1-(5-chloro-3-(2-methoxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.185 g, 0.422 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added. The reaction was stirred at room temperature for1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-50CH₃CN/water). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirred solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give(R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxyacetamidehydrochloride (0.170 g, 98% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.10 (s, 1H), 7.41 (s, 1H), 4.09 (s, 2H), 3.71-3.68 (m, 1H), 3.49-3.46(m, 1H), 3.40 (s, 3H), 3.27-3.13 (m, 3H), 2.11-2.08 (m, 1H), 1.78-1.75(m, 1H), 1.67-1.65 (m, 1H), 1.54-1.50 (m, 1H). LCMS (APCI+) m/z 338(M+H)+.

Example 97

(S)—N-(4-((R)-3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide

Step A: An NMP solution (2 mL) of (R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.200 g, 0.547 mmol; Example 91, Step A), (S)-2-methoxypropanoic acid(0.310 mL, 3.28 mmol), BOP-Cl (0.835 g, 3.28 mmol), and triethylamine(0.533 mL, 3.83 mmol) was stirred for 18 hours. 3M aqueous LiOH (3 mL)was then added. The reaction was stirred for 10 minutes, poured intowater, and extracted with DCM. The combined organic fractions were dried(MgSO₄), filtered, and concentrated to give the crude product, which waspurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95CH₃CN/water) to give the product tert-butyl(R)-1-(5-chloro-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.190 g, 77%yield).

Step B: tert-Butyl(R)-1-(5-chloro-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.190 g, 0.420 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added. The reaction was stirred at room temperature for1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95CH₃CN/water). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirred solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give(S)—N-(4-((R)-3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamidehydrochloride (0.100 g, 56% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.09 (s, 1H), 7.46 9s, 1H), 4.05-3.99 (q, 1H), 3.67-3.64 (m, 1H),3.51-3.49 (m, 1H), 3.37 (s, 3H), 3.26-3.21 (m, 3H), 2.11-2.08 (m, 1H),1.81-1.77 (m, 1H), 1.72-1.67 (m, 1H), 1.53-1.50 (m, 1H). LCMS (APCI+)m/z 352 (M+H)+.

Example 98

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)butyramide

Step A: (R)-tert-Butyl piperidin-3-ylcarbamate (7.84 g, 39.12 mmol) andN,N-diisopropylethylamine (5.06 g, 6.82 mL, 39.12 mmol) were added to asolution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (3.00 g,13.04 mmol; Example 1, Step H) in NMP (32 mL). The resulting mixture washeated at 120° C. on an oil bath under a nitrogen atmosphere for 18hours. The crude reaction mixture was used in the next step. LCMS(APCI+) m/z 410 (M+H)+, Retention time=3.32 minutes.

Step B: Butyryl chloride (234 mg, 2.19 mmol) in anhydrousdichloromethane (0.5 mL) was added dropwise to a solution of(R)-tert-butyl1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(150 mg, 0.366 mmol) and triethylamine (259 mg, 0.357 mL, 2.56 mmol) inNMP (0.900 mL) cooled on an ice-bath. The mixture was stirred at ambienttemperature for 1 hour. The mixture was diluted with THF (10 mL),treated with an aqueous 2N LiOH solution (3 mL) and stirred for 1 hour.The THF was evaporated. The residue was stirred with water (20 mL) andextracted with EtOAc (3×20 mL). The combined organic extracts were driedover MgSO₄, filtered and concentrated. The residue was purified byreverse phase chromatography (Biotage SP4, C-18 25M+, 15-80%CH₃CN/water, 25CV) to give (R)-tert-butyl1-(5-bromo-3-butyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(176 mg, 100% yield) as a solid. LCMS (APCI+) m/z 482.1, 382, 380(M+H)+, Retention time=3.80 minutes.

Step C: (R)-tert-Butyl1-(5-bromo-3-butyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(176 mg, 0.366 mmol) was stirred in TFA (3 mL) at room temperature for1.5 hours. The solvent was evaporated in vacuo, and the residue purifiedby reverse phase chromatography (Biotage SP4, C-18 12M+, 2-50%CH₃CN/water, 16CV). The isolated product was taken up in a minimalvolume of methanol and added to a stirred solution of 2N HCl-Et₂O. Thesalt formed was collected by filtration, washed with acetonitrile anddried under vacuum to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-1-pyrrolo[2,3-b]pyridin-3-yl)butyramide(110 mg, 66% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ 8.27 (s, 1H),7.54 (s, 1H), 3.52-3.23 (m, 4H), 3.15-3.05 (m, 1H), 2.38 (t, 2H),2.19-2.10 (m, 1H), 1.93-1.85 (m, 1H), 1.78-1.60 (m, 3H), 1.58-1.42 (m,1H), 0.97 (t, 3H). LCMS (APCI+) m/z 380, 383.1 (M+H)+, Retentiontime=2.38 minutes.

Example 99

(R)-1-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-ethylurea

Step A: (R)-tert-Butyl1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.150 g, 0.366 mmol; Example 98, Step A) was placed in 1:1 NMP:pyridine(2 mL total volume). Isocyanatoethane (0.146 mL, 1.83 mmol) was thenadded, and the reaction was stirred at room temperature for 30 minutesand then concentrated. The residue was purified by reverse phasechromatography (Biotage SP4, C-18 12M+, 5:95 ACN in water) to give(R)-tert-butyl1-(5-bromo-3-(3-ethylureido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.130 g, 74% yield).

Step B: (R)-tert-Butyl1-(5-bromo-3-(3-ethylureido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.130 g, 0.270 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added. The reaction was stirred at room temperature for1 hour and concentrated to dryness. The residue was then purified byreverse phase chromatography (Biotage SP4, C-18 12M+, 0-50% ACN inwater). The resulting product was next dissolved in minimal DCM (withMeOH to aid solubility) and added to a stirring solution of 1M HCl inether. The resulting solid was filtered, washed with ether and dried togive(R)-1-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-ethylureahydrochloride (0.100 g, 81.5% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.27 (s, 1H), 7.27 (s, 1H), 3.86-3.83 (m, 1H), 3.56-3.54 (m, 1H),3.48-3.45 (m, 1H), 3.26-3.21 (m, 2H), 3.04-2.99 (m, 2H), 2.09-2.06 (m,1H), 1.81-1.70 (m, 2H), 1.57-1.55 (m, 1H), 0.94-0.90 (m, 3H). LCMS(APCI+) m/z 381, 383 (M+H)+.

Example 100

(S)—N-(4-((R)-3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxypropanamide

Step A: (R)-tert-Butyl1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.200 g, 0.487 mmol; Example 98, Step A), (S)-2-acetoxypropanoic acid(0.386 g, 2.92 mmol), BOP-Cl (0.745 g, 2.92 mmol), and triethylamine(0.679 mL, 4.87 mmol) were placed in DCM (6 mL) and stirred at roomtemperature for 18 hours. 3M aqueous LiOH (6 mL) was then added. Thereaction was stirred for 10 minutes, poured into water, and extractedwith DCM. The combined organic fractions were dried (MgSO₄), filtered,and concentrated to give the crude product, which was purified byreverse phase chromatography (Biotage SP4, C-18 25M+, 5-95 CH₃CN/water)to give tert-butyl(R)-1-(5-bromo-3-((S)-2-hydroxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.120 g, 51% yield).

Step B: tert-Butyl(R)-1-(5-bromo-3-((S)-2-hydroxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.120 g, 0.249 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added. The reaction was stirred at room temperature for1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-50CH₃CN/water). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirred solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give(S)—N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxypropanamideHCl (0.070 g, 62% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ 8.20 (s,1H), 7.48 (s, 1H), 4.37-4.32 (q, 1H), 3.61-3.55 (m, 2H), 3.31-3.24 (m,2H), 3.16-3.13 (m, 1H), 2.09-2.05 (m, 1H), 1.77-1.71 (m, 2H), 1.54-1.51(m, 1H), 1.35-1.33 (d, 3H). LCMS (APCI+) m/z 382, 384 (M+H)+.

Example 101

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-(prop-1-en-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

Step A: 4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (174mg, 1.03 mmol), PS-palladium tetrakis (470 mg, 0.0517 mmol, 0.10 mmol/1g) and 2N sodium carbonate (775 μL, 1.55 mmol) were added to(R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(300 mg, 0.517 mmol; Example 81, Step A) in degassed dioxane (1 mL). Thereaction was heated to 120° C. for 1 hour under microwave irradiation.4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (174 mg, 1.03mmol) and 2N sodium carbonate (775 μL, 1.55 mmol) were added, and thereaction was heated to 120° C. for an additional 2 hours. The reactionmixture was then cooled down and filtered. The filtrate was diluted withDCM washed with water. The layers were separated. The organic phase wasdried (MgSO₄) and concentrated, and the resulting residue was purifiedby reverse phase chromatography (Biotage SP4, C-18 25M+, 15-100%CH₃CN/water) to yield (R)-tert-butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-5-(prop-1-en-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(141 mg, 50% yield) as a solid.

Step B: (R)-tert-Butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-5-(prop-1-en-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(20 mg, 0.0369 mmol) was placed in TFA (2 mL) and stirred for 30minutes. The reaction was concentrated and redissolved in 10% MeOH inDCM. This solution was added dropwise to a stirred solution of 2M HCl inether. The reaction was then concentrated and dried to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-(prop-1-en-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (13.8 mg, 90% yield) as a solid. ¹H NMR (400 MHz,(CD₃)₂SO) δ 11.96 (s, 1H), 9.36 (s, 1H), 8.21 (br s, 2H), 7.92 (s, 1H),7.51 (s, 1H), 5.35 (s, 1H), 4.94 (s, 1H), 3.55 (m, 1H), 3.38 (m, 2H),3.20-3.05 (m, 2H), 2.72 (m, 1H), 2.06 (m, 1H), 1.83 (m, 1H), 1.70 (m,1H), 1.50 (m, 1H), 1.14 (dd, 6H). LCMS (APCI+) m/z 342.1 (M+H)+,Retention time=2.13 minutes (Method 3).

Example 102

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

(R)-tert-Butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-isobutyramido-5-(prop-1-en-2-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(125 mg, 0.231 mmol; Example 101, Step A), Pd/C (123 mg, 0.115 mmol),and ethanol (5 mL) were placed under about 1 to 2 atm of hydrogenpressure (balloon) for 24 hours. An extra 0.5 equivalents of Pd/C (61.5mg, 0.058 mmol) were then added, and the reaction was stirred for anadditional 16 hours. The reaction mixture was filtered and concentrated,and the resulting residue was purified by reverse phase chromatography(Gilson, C-18, 0-95% CH₃CN/water with 0.1% TFA). The product was thendissolved in 10% MeOH in DCM (2 mL) and added dropwise to a solution of2M HCl in ether. The reaction was concentrated to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (29.1 mg, 30% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.07 (s, 1H), 7.33 (s, 1H), 3.52 (m, 1H), 3.39 (m, 1H), 3.21 (m, 2H),3.09 (m, 2H), 2.66 (m, 1H), 2.10 (m, 1H), 1.79 (m, 1H), 1.69 (m, 1H),1.51 (m, 1H), 1.15 (t, 6H), 1.11 (dd, 6H). LCMS (APCI+) nm/z 344.2(M+H)+, Retention time=2.26 minutes (Method 3).

Example 103

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-2-methylpropanamide

Step A: A solution of 1-chloro-2-methyl-1-oxopropan-2-yl acetate (540mg, 0.469 mL, 3.28 mmol) in anhydrous dichloromethane (2 mL) was addeddropwise to a solution of (R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(200 mg, 547 mmol; Example 91, Step A) and triethylamine (387 mg, 0.533mL, 3.83 mmol) in NMP (15 mL) cooled on an ice-bath. The mixture wasstirred at ambient temperature for 2 hours. THF (10 mL) was added. Themixture treated with an aqueous solution of 2N LiOH (10 mL) and stirredovernight. The mixture was diluted with water and extracted with EtOAc(3×30 mL). The combined organic extracts were dried over MgSO₄,filtered, and concentrated. The residue was purified by reverse phasechromatography (Biotage SP4, C-18 25M+, 20-75% CH₃CN/water, 25CV) togive (R)-tert-butyl1-(5-chloro-3-(2-hydroxy-2-methylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(221 mg, 89% yield) as a solid. LCMS (APCI+) m/z 452, 454 (M+H)+,Retention time=3.44 minutes.

Step B: (R)-tert-Butyl1-(5-chloro-3-(2-hydroxy-2-methylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(221 mg, 0.489 mmol) was stirred in trifluoroacetic acid (3 mL) at roomtemperature for 1.5 hours. The solvent was evaporated in vacuo, and theresidue was purified by reverse phase chromatography (Biotage SP4, C-1825M+, 2-55% CH₃CN/water, 25CV). The isolated product was taken up in aminimal volume of methanol and added to a stirred solution of 2NHCl-Et₂O. The salt formed was collected by filtration, washed withacetonitrile and dried under vacuum to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-2-methylpropanamidehydrochloride (103 mg, 50% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.05 (s, 1H), 7.53 (s, 1H), 3.64-3.48 (m, 2H), 3.53-3.22 (m, 1H),3.24-3.16 (m, 1H), 3.12-3.04 (m, 1H), 2.12-2.04 (m, 1H), 1.80-1.66 (m,2H), 1.56-1.44 (m, 1H), 1.38 (s. 3H), 1.35 (s, 3H). LCMS (APCI+) m/z352.1, 354.1 (M+H)+, Retention time 2.02 minutes.

Example 104

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-(methylthio)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide

(R)-tert-Butyl1-(5-bromo-3-(2-cyclopropylacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(225 mg, 0.457 mmol; Example 58, Step B) was dissolved in THF (25 mL)and cooled to −78° C. MeLi (1142 μL, 1.83 mmol) was slowly added. Thereaction was stirred for 10 minutes. n-Butyl lithium (366 μL, 0.914mmol) was slowly added. The reaction was stirred for 10 minutes, andthen 1,2-dimethyldisulfane (129 mg, 1.37 mmol) was added. The reactionwas stirred for 30 minutes and then quenched with water. The reactionmixture was extracted several times with DCM. The organic layer wasdried, filtered, and concentrated. The residue was purified by reversephase chromatography (Gilson, C-18, 0-95% CH₃CN/water with 0.1% TFA).The product was then dissolved in 10% MeOH in DCM (2 mL) and addeddropwise to a solution of 2M HCl in ether. The reaction was concentratedto give(R)—N-(4-(3-aminopiperidin-1-yl)-5-(methylthio)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamidehydrochloride (45 mg, 23% yield). ¹H NMR (400 MHz, D₂O) δ 7.96 (s, 1H),7.14 (s, 1H), 3.71 (d, 1H), 3.50 (m, 1H), 3.24 (m, 1H), 3.08-2.96 (m,2H), 2.21 (s, 3H), 2.16 (d, 2H), 1.93 (m, 1H), 1.68 (m, 1H), 1.54-1.39(m, 2H), 0.83 (m, 1H), 0.37 (m, 214), 0.01 (m, 2H). LCMS (APCI+) m/z360.1 (M+H)+, Retention time=2.19 minutes (Method 3).

Example 105

(R)—N-(5-Bromo-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

Step A: A 250 mL round bottom flask was charged with5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (1.00 g, 4.35 mmol;Example 1, Step H), (R)-tert-butyl methyl(piperidin-3-yl)carbamate (1.86g, 8.69 mmol), N-ethyl-N-isopropylpropan-2-amine (2.27 mL, 13.0 mmol),and NMP (10.8 mL). Nitrogen was bubbled through the mixture for 5minutes. The reaction was stirred at 125° C. (oil bath) under positivenitrogen atmosphere for 20 hours to provide the crude (R)-tert-butyl1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate.

Step B: A solution of (R)-tert-butyl1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(305 mg, 0.7188 mmol) in NMP (3 mL) was cooled to 0° C. and pyridine(1.5 mL) was added. Then the mixture was treated dropwise withcyclopropanecarbonyl chloride (195.7 μL, 2.156 mmol) and stirred at 0°C. for 30 minutes. 2M LiOH.H₂O (4 mL) was then added, and the mixturewas stirred at room temperature. After 48 hours, the mixture was dilutedwith EtOAc (100 mL) and washed with water (3×20 mL). The organic layerwas separated, dried (MgSO₄), filtered, and concentrated in vacuo. Theresidue was purified by reverse phase chromatography (Biotage SP4, C-1840M+, 15-85% CH₃CN/water, 35 CV) to provide (R)-tert-butyl1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamatehydrochloride (127 mg, 36% yield) as a solid. LCMS (APCI+) m/z 492(M+H)+.

Step C: A solution of (R)-tert-butyl1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(125 mg, 0.254 mmol) in neat TFA (3 mL) was stirred at room temperaturefor 30 minutes and concentrated in vacuo. The oily residue was dissolvedin CH₂Cl₂ and evaporated form CH₃CN (5 mL) to give(R)—N-(5-bromo-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (90 mg, 76% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.81 (s, 1H), 9.62 (s, 1H), 9.21-9.01 (m, 2H), 8.23 (s, 1H), 7.49 (s,1H), 3.58-3.51 (m, 1H), 3.48-3.22 (m, 3H), 3.10-3.05 (m, 1H), 2.57 (t,3H), 2.27-2.21 (m, 1H), 1.91-1.82 (m, 2H), 1.78-1.65 (m, 1H), 1.55-1.43(m, 1H), 0.83 (d, 4H). LCMS (APCI+) m/z 392.1, 394.1 (M+H)+.

Example 106

N-(4-(Trans-3-amino-4-cyclopropylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

A mixture ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (0.20 g,0.67 mmol; Example 15, Step A),tert-butyl-trans-4-cyclopropylpiperidin-3-ylcarbamate (0.48 g, 2.00mmol; Example K) and DIEA (0.35 mL, 2.00 mmol) in n-BuOH (2 mL) wasstirred at 146° C. (bath) for 20 hours. The solvent was removed. Theresidue was dissolved in ethyl acetate (20 mL), washed with water (10mL), brine (10 mL), dried (sodium sulfate) and concentrated in vacuo.The residue was purified by reverse phase chromatography (Biotage SP4,C-18 25M+, 20-80% CH₃CN/water, 25 CV). The product isolated wasdissolved in DCM (2 mL), and TFA (0.5 mL) was added. The mixture wasstirred at room temperature for 1 hour. The solvent was removed. Theresidue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) wasadded. The solid formed was collected to giveN-(4-(trans-3-amino-4-cyclopropylpiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (0.17 g, 52%) as a solid. ¹H NMR (400 MHz, D₂O) δ 8.21 (s,1H), 7.26 (s, 1H), 3.81 (m, 1H), 3.48 (m, 1H), 3.38 (m, 1H), 3.11 (m,2H), 2.60 (m, 1H), 1.88 (m, 1H), 1.82 (m, 1H), 1.52 (m, 1H), 1.16 (m,1H), 1.07 (t, 6H), 0.77 (m, 1H), 0.39 (m, 1H), 0.14 (m, 1H), 0.11 (m,1H). LCMS (APCI+) m/z 420 (M+H)+.

Example 107

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

Step A: di-tert-Butyl dicarbonate (150 mg, 0.687 mmol), DMAP (21 mg,0.172 mmol) and triethylamine (174 mg, 0.239 mL, 1.72 mmol) were addedto a solution of (R)-tert-butyl1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(274 mg, 0.573 mmol; Example 29, Step B) in anhydrous dichloromethane (6mL). The resulting mixture was stirred at room temperature under anitrogen atmosphere for 2 hours. The mixture was concentrated. Theresidue was taken up in EtOAc, washed with water (3×10 mL) and brine(3×10 mL), dried over MgSO₄ and filtered. The filtrate was concentratedunder reduced pressure, and the residue was purified by reverse phasechromatography (Biotage SP4, C-18 25M+, 20-95% CH di-tert-butyldicarbonate (150 mg, 0.687 mmol), DMAP (21 mg, 0.172 mmol) andtriethylamine (174 mg, 0.239 mL, 1.72 mmol) CN/water, 25CV) to give(R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(237 mg, 71% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 10.03 (br s,1H), 8.48 (s, 1H), 8.19 (s, 1H), 3.93-3.73 (m, 1H), 3.67-3.45 (m, 1H),3.41-3.30 (m, 1H), 3.06-2.99 (m, 1H), 2.27-2.17 (m, 1H), 2.06-1.95 (m,1H), 1.90-1.77 (m, 1H), 1.63 (s, 9H), 1.60 (s, 1H), 1.42 (s, 9H),1.22-1.05 (m, 2H), 1.03-0.85 (m, 2H). LCMS (APCI+) m/z 580 (M+2H)+,Retention time=4.53 minutes.

Step B: A solution of (R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonyl-amino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(200 mg, 0.346 mmol), potassium trifluoro(vinyl)borate (60 mg, 0.449mmol), PdCl₂(dppf) dichloromethane adduct (31 mg, 0.038 mmol) andtriethylamine (39 mg, 0.053 mL, 0.38 mmol) in ethanol (6 mL) was heatedat 100° C. under nitrogen for 18 hours. The mixture was cooled to roomtemperature and evaporated under reduced pressure. The residue waspurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 20-80%CH₃CN/water, 25CV) to give (R)-tert-butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-5-vinyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(64 mg, 35% yield) as a solid. LCMS (APCI+) m/z 526 (M+H)+, Retentiontime=4.53 minutes.

Step C: 10% Pd/C (65 mg, 0.061 mmol) was added to a solution of(R)-tert-butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-5-vinyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(64 mg, 0.12 mmol) in ethanol (6 mL). The mixture was stirred under ahydrogen atmosphere (balloon) for 3.5 hours. The mixture was filteredthrough a pad of Celite® and washed with methanol, and the filtrateevaporated in vacuo. The residue was purified by reverse phasechromatography (Biotage SP4, C-18 25M+, 15-80% CH₃CN/water, 25CV) togive (R)-tert-butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-5-ethyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(29.4 mg, 46% yield) as a solid. LCMS (APCI+) m/z 528 (M+H)+, Retentiontime=4.37 minutes.

Step D: (R)-tert-Butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-5-ethyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(29 mg, 0.056 mmol) was stirred at room temperature in trifluoroaceticacid (1.5 mL) for 1.5 hours. The acid was removed in vacuo, and theresidue was purified by C-18 flash chromatography (12M+) on a BiotageSP4 eluting with a gradient of 2-50% CH₃CN/water (16CV). The isolatedproduct was taken up in a minimal volume of methanol and added to astirred solution of 2N HCl-Et₂O. The salt formed was collected byfiltration, washed with acetonitrile and dried under vacuum to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (22 mg, 98% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 12.27 (br s, 1H), 9.93 (s, 1H), 8.40 (br s, 1H), 8.11 (s, 1H), 7.47(d, 1H), 3.73-3.65 (m, 1H), 3.48-3.35 (m, 1H), 3.32-3.10 (m, 3H), 2.78(q, 2H), 2.20-2.10 (m, 1H), 1.99-1.89 (m, 1H), 1.88-1.80 (m, 1H),1.78-1.64 (m, 1H), 1.62-1.48 (m, 1H), 1.22 (t, 3H), 0.90-0.75 (m, 4H).LCMS (APCI+) m/z 328.1, 329.1 (M+H)+, Retention time=2.28 minutes.

Example 108

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyanoacetamide

Step A: 2-Cyanoacetic acid (0.332 g, 3.90 mmol), BOP-Cl (0.993 g, 3.90mmol), and triethylamine (1.02 mL, 7.31 mmol) were added to an NMPsolution (2 mL) of (R)-tert-butyl1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.200 g, 0.487 mmol; Example 98, Step A). The reaction was then stirredfor 18 hours, then poured into water, and extracted with DCM. Thecombined organic fractions were dried (MgSO₄), filtered, andconcentrated to give the crude product, which was purified by reversephase chromatography (Biotage SP4, C-18 25M+, 5-95% CH₃CN/water) to give(R)-tert-butyl1-(5-bromo-3-(2-cyanoacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.06 g, 26% yield).

Step B: (R)-tert-Butyl1-(5-bromo-3-(2-cyanoacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.050 g, 0.10 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added. The reaction was stirred at room temperature for1 hour and then concentrated to dryness. The resulting residue was thenpurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 5-50%CH₃CN/water). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirring solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyanoacetamidehydrochloride (0.035 g, 74% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.24 (s, 1H), 7.32 (s, 1H), 3.83 (s. 2H), 3.73-3.70 (m, 1H), 3.56-3.54(m, 1H), 3.32-3.29 (m, 1H), 3.24-3.13 (m, 2H), 2.10-2.07 (m, 1H),1.83-1.79 (m, 1H), 1.67-1.55 (m, 2H). LCMS (APCI+) m/z 377, 379 (M+H)+.

Example 109

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)butyramide

Step A: Butyryl chloride (350 mg, 3.28 mmol) in anhydrousdichloromethane (0.5 mL) was added dropwise to a solution of(R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(200 mg, 0.547 mmol; Example 91, Step A) and triethylamine (387 mg.0.533 mL, 3.83 mmol) in NMP (1.0 mL) cooled on an ice-bath. Theresulting mixture was stirred at ambient temperature for 1 hour. Themixture was diluted with THF (10 mL), treated with an aqueous 2N LiOHsolution (3 mL) and stirred for 1 hour. The THF was evaporated, and theresidue was stirred with water (20 mL) and extracted with EtOAc (3×20mL). The combined organic extracts were dried over MgSO₄, filtered andconcentrated. The residue was purified by reverse phase chromatography(Biotage SP4, C-18 25M+, 15-80% CH₃CN/water, 25CV) to yield(R)-tert-butyl1-(3-butyramido-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(221 mg, 93% yield) as a solid. LCMS (APCI+) m/z 336.1, 436.1 (M+H)+,Retention time=3.75 minutes.

Step B: (R)-tert-Butyl1-(3-butyramido-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(221 mg, 0.507 mmol) was stirred in TFA (3 mL) at room temperature for1.5 hours. The solvent was evaporated in vacuo, and the residue purifiedby reverse phase chromatography (Biotage SP4, C-18 12M+, 2-50%CH₃CN/water, 16CV). The isolated product was taken up in a minimalvolume of methanol and added to a stirred solution of 2N HCl-Et₂O. Thesalt formed was collected by filtration, washed with acetonitrile anddried under vacuum to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)butyramide(153 mg, 74% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.83 (brs, 1H), 9.32 (s, 1H), 8.35 (br s, 2H), 8.13 (s, 1H), 7.57 (s, 1H),3.54-3.46 (m, 1H), 3.45-3.30 (m, 2H), 3.27-3.04 (m, 2H), 2.41-2.34 (m,2H), 2.18-2.09 (m, 1H), 1.91-1.79 (m, 1H), 1.72-1.59 (m, 3H), 1.59-1.39(m, 1H), 0.96 (t, 3H). LCMS (APCI+) m/z 336.1, 338.1 (M+H)+, Retentiontime=2.38 minutes.

Example 110

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)propionamide

Step A: DCM (2 mL), pyridine (0.5 mL) and propionyl chloride (0.180 g,1.95 mmol) were added to (R)-tert-butyl1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.200 g, 0.487 mmol; Example 98, Step A) in NMP (3 mL). The reactionwas then stirred for 1 hour at room temperature. 3M aqueous LiOH (3 mL)was then added, and the reaction was stirred for 10 minutes. Water (10mL) and DCM (10 mL) were then added, and the organic fraction was dried,filtered and concentrated to give the crude product. Purification byreverse phase HPLC (5-95% ACN in water) gave the product (R)-tert-butyl1-(5-bromo-3-propionamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.120 g, 52.8% yield).

Step B: (R)-tert-butyl1-(5-bromo-3-propionamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.150 g, 0.322 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added. The reaction was stirred at room temperature for1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase HPLC (0-50% ACN in water). The resultingproduct was next dissolved in minimal DCM (with MeOH to aid solubility)and added to a stirring solution of 1M HCl in ether. The resulting solidwas filtered, washed with ether and dried to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)propionamidehydrochloride (0.110 g, 77.9% yield). ¹H NMR (400 MHz, D₂O) δ 8.24 (s,1H), 7.27 (s, 1H), 3.74-3.71 (m, 1H), 3.56-3.52 (m, 1H), 3.33-3.30 (m,1H), 3.20-3.15 (m, 2H), 2.42-2.37 (q, 2H), 2.08-2.06 (m, 1H), 1.80-1.76(m, 1H), 1.67-1.54 (m, 2H), 1.10-1.06 (t, 3H). LCMS (APCI+) m/z 366, 368(M+H)+.

Example 111

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)propionamide

Step A: DCM (2 mL) and pyridine (1 mL) were added to (R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.3 g, 0.820 mmol; Example 91, Step A) in NMP (2 mL), and thenpropionyl chloride (0.228 g, 2.46 mmol) was added. The reaction was thenstirred for 1 hour at room temperature, and then 3M aqueous LiOH (3 mL)was added. The reaction was stirred for 10 minutes. Water (10 mL) andDCM (10 mL) were then added, and the organic fraction was dried,filtered and concentrated. Purification of the crude product by reversephase HPLC (5-95% ACN in water) gave the product (R)-tert-butyl1-(5-chloro-3-propionamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.220 g, 63.6% yield).

Step B: (R)-tert-Butyl1-(5-chloro-3-propionamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.22 g, 0.521 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added, and the reaction was stirred at room temperaturefor 1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase HPLC (0-50% ACN in water). The resultingproduct was next dissolved in minimal DCM (with MeOH to aid solubility)and added to a stirring solution of 1M HCl in ether. The resulting solidwas filtered, washed with ether and dried to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)propionamidehydrochloride (0.190 g, 92.3% yield). ¹H NMR (400 MHz, D₂O) δ 8.14 (s,1H), 7.28 (s, 1H), 3.88-3.84 (m, 1H), 3.54-3.37 (m, 2H), 3.19-3.13 (m,2H), 2.42-2.37 (q, 2H), 2.11-2.08 (m, 1H), 1.80-1.76 (m, 1H), 1.66-1.54(m, 2H), 1.10-1.06 (t, 3H). LCMS (APCI+) m/z 322 (M+H)+.

Example 112

(R)—N-(5-Chloro-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

Step A: 5-Chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.60 g, 3.2mmol; Example 8, Step D), (R)-tert-butyl methyl(piperidin-3-yl)carbamate(2.1 g, 9.7 mmol) and DIEA (1.7 mL, 9.7 mmol, d 0.742) were placed inNMP (6 mL) and heated to 120° C. for 20 hours. The reaction was thencooled to room temperature, and the crude NMP solution of (R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamatewas used in the next step without further purification.

Step B: Pyridine (1 mL) and cyclopropanecarbonyl chloride (0.413 g, 3.95mmol) were added to (R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(0.300 g, 0.790 mmol) in NMP (2 mL), and the reaction was stirred atroom temperature for 1 hour. 3M aqueous LiOH (3 mL) was then added, andthe reaction was stirred for 10 minutes. Water (10 mL) and DCM (10 mL)were then added, and the organic fraction was separated, dried,filtered, and concentrated. The crude residue was purified by reversephase chromatography (Biotage SP4, C-18 25M+, 5-95% CH₃CN/water) to give(R)-tert-butyl1-(5-chloro-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(0.170 g, 48% yield).

Step C: (R)-tert-Butyl1-(5-chloro-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(0.150 g, 0.335 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added, and the reaction was stirred at room temperaturefor 1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-50%CH₃CN/water). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirred solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give(R)—N-(5-chloro-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (0.120 g, 85% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.12 (s, 1H), 7.27 (s, 1H), 3.87-3.84 (m, 1H), 3.42-3.37 (m, 2H),3.22-3.17 (m, 2H), 2.60 (s, 3H), 2.18-2.15 (m, 1H), 1.82-1.67 (m, 3H),1.56-1.53 (m, 1H), 0.91-0.80 (m, 4H). LCMS (APCI+) m/z 348 (M+H)+.

Example 113

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-(methylthio)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

(R)-tert-Butyl1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(820 mg, 1.71 mmol; Example 15, Step B) was dissolved in THF (35 mL) andcooled to −78° C. MeLi (4285 μL, 6.86 mmol) was slowly added, and thereaction was stirred for 10 minutes. n-Butyl lithium (1714 j-L, 4.29mmol) was slowly added, and the reaction was stirred for 1 minute.1,2-Dimethyldisulfane (646 mg, 6.86 mmol) was then added. The reactionwas stirred for 30 minutes and then quenched with water. The aqueousphase was extracted several times with DCM. The combined organic layerswere dried (MgSO₄), filtered, and concentrated. The residue was purifiedby C-18 reverse phase flash chromatography (Gilson prep LC, eluting with5-95 gradient water:ACN with 0.1% TFA over 20 minutes). The resultingsolid was dissolved in TFA (2 mL) and stirred for 20 minutes. Thereaction mixture was then concentrated, and the residue dissolved in 10%MeOH in DCM and added to a stirring solution of 2M HCl in ether.Concentration gave(R)—N-(4-(3-aminopiperidin-1-yl)-5-(methylthio)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (177 mg, 24.7% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.10 (s, 1H), 7.27 (s, 1H), 3.84 (m, 1H), 3.61 (m, 1H), 3.39 (m, 1H),3.18 (m, 2H), 2.34 (s, 3H), 2.08 (m, 1H), 1.86-1.53 (m, 4H), 0.92-0.77(m, 4H). LCMS (APCI+) m/z 346.1 (M+H)+, Retention time=1.97 minutes(Method 3).

Example 114

(R)-Ethyl4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamate

Step A: (R)-tert-Butyl1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.200 g, 0.487 mmol; Example 98, Step A) and triethylamine (0.204 mL,1.46 mmol) were placed in DCM (5 mL), followed by the addition ofdiethyl dicarbonate (0.237 g, 1.46 mmol). The reaction was stirred atroom temperature for 1 hour. The reaction was then poured into water andextracted with EtOAc. The combined organic fractions were dried (MgSO₄),filtered, and concentrated to give the crude product, which was purifiedby reverse phase chromatography (Biotage SP4, C-18 25M+, 5-95%CH₃CN/water) to give (R)-tert-butyl1-(5-bromo-3-(ethoxycarbonylamino)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.130 g, 55% yield).

Step B: (R)-tert-Butyl1-(5-bromo-3-(ethoxycarbonylamino)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.120 g, 0.249 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added, and the reaction was stirred at room temperaturefor 1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-50%CH₃CN/water). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirred solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give (R)-ethyl4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-ylcarbamatehydrochloride (0.090 g, 79% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.23 (s, 1H), 7.28 (s, 1H), 4.11-4.06 (q, 2H), 3.78-3.75 (m, 1H),3.53-3.49 (m, 1H), 3.40-3.43 (m, 1H), 3.27-3.18 (m, 2H), 2.09-2.06 (m,1H), 1.81-1.69 (m, 2H), 1.60-1.54 (m, 1H), 1.19-1.16 (t, 3H). LCMS(APCI+) m/z 382, 384 (M+H)+.

Example 115

(R)—N-(5-Chloro-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)propionamide

Step A: (R)-tert-Butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(0.300 g, 0.790 mmol; Example 112, Step A) in NMP (2 mL), pyridine (1mL) and propionyl chloride (0.365 g, 3.95 mmol) were stirred at roomtemperature for 1 hour. 3M aqueous LiOH (3 mL) was then added, and thereaction was stirred for 10 minutes. Water (10 mL) and DCM (10 mL) werethen added, and the organic fraction was separated, dried, filtered, andconcentrated. The crude residue was purified by reverse phasechromatography (Biotage SP4, C-18 25M+, 0-95% CH₃CN/water) to give(R)-tert-butyl1-(5-chloro-3-propionamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(0.160 g, 46% yield).

Step B: (R)-tert-Butyl1-(5-chloro-3-propionamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(0.180 g, 0.413 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added, and the reaction was stirred at room temperaturefor 1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-50%CH₃CN/water). The resulting product was dissolved in minimal DCM (withMeOH to aid solubility) and added to a stirred solution of 1M HCl inether. The resulting solid was filtered, washed with ether and dried togive(R)—N-(5-chloro-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)propionamidehydrochloride (0.150 g, 89% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.13 (s, 1H), 7.28 (s, 1H), 3.87-3.84 (m, 1H), 3.42-3.37 (m, 2H),3.20-3.14 (m, 2H), 2.59 (s, 3H), 2.42-2.37 (q, 2H), 1.15-2.13 (m, 1H),1.79-1.75 (m, 1H), 1.65-1.52 (m, 2H), 1.10-1.06 (t, 3H). LCMS (APCI+)m/z 336 (M+H)+.

Example 116

(R)—N-(5-Chloro-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

Step A: Pyridine (1 mL) and isobutyryl chloride (0.421 g, 3.95 mmol)were added to (R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate (0.300 g, 0.790 mmol; Example 112, Step A) in NMP (2 mL), andthe reaction was stirred at room temperature for 1 hour. 3M aqueous LiOH(3 mL) was then added, and the reaction was stirred for 10 minutes.Water (10 mL) and DCM (10 mL) were then added, and the organic layer wasseparated, dried, filtered and concentrated. The crude residue waspurified by reverse phase chromatography (Biotage SP4, C-18 12M+, 5-95%CH₃CN/water) to give (R)-tert-butyl1-(5-chloro-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(0.180 g, 51% yield).

Step B: (R)-tert-Butyl1-(5-chloro-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate(0.180 g, 0.400 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added, and the reaction was stirred at room temperaturefor 1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase chromatography (Biotage SP4, C-18 12M+, 0-50%CH₃CN/water). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirred solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give(R)—N-(5-chloro-4-(3-(methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (0.150 g, 89% yield) as a solid. ¹H NMR (400 MHz, D₂₀) δ8.16 (s, 1H), 7.28 (s, 1H), 4.01-3.98 (m, 1H), 3.49-3.37 (m, 2H),3.21-3.11 (m, 2H), 2.69-2.65 (m, 1H), 2.60 (s, 3H), 2.19-2.16 (m, 1H),1.82-1.78 (m, 1H), 1.64-1.51 (m, 2H), 1.12-1.08 (m, 6H). LCMS (APCI+)m/z 350 (M+H)+.

Example 117

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-(isopropylthio)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

(R)-tert-Butyl1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(150 mg, 0.314 mmol; Example 29, Step B),(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (18.1 mg,0.0314 mmol), Pd₂dba₃ (14.4 mg, 0.0157 mmol), propane-2-thiol (71.6 mg,0.941 mmol), and N-ethyl-N-isopropylpropan-2-amine (109 μL, 0.627 mmol)were placed in dioxane (1 mL) and heated to 150° C. under microwaveirradiation for 2 hours. DCM and water were then added to the reactionmixture. The layers were separated, and the organic was washed with 1MNaOH. The organic layer was dried, filtered, and concentrated. Theresidue was purified by reverse phase chromatography (Biotage SP4, C-1825M+, 5-95% CH₃CN/water). The product was then dissolved in TFA (2 mL)and stirred for 15 minutes. The reaction was concentrated, and theresulting residue was dissolved in 10% MeOH in DCM and then addeddropwise to a stirred solution of 2M HCl in ether. The reaction wasconcentrated to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-(isopropylthio)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (72 mg, 51% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.21 (s, 1H), 7.27 (s, 1H), 3.91 (d, 11H), 3.65 (m, 1H), 3.52 (d, 1H),3.27-3.09 (m, 3H), 2.15 (m, 1H), 1.81-1.70 (m, 3H), 1.57 (m, 1H), 1.08(dd, 6H), 0.94-0.80 (m, 4H). LCMS (APCI+) m/z 374.1 (M+H)+, Retentiontime=2.38 minutes (Method 3).

Example 118

(R)—N-(4-((R)-3-Aminopiperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide

Step A: TEA (0.82 mL, 5.91 mmol) was added to a mixture of4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.20 g, 1.18 mmol;Example 13, Step C), (R)-2-methoxypropanoic acid (0.25 g, 2.37 mmol) andBOP-Cl (0.60 g, 2.37 mmol) in DCM (5 mL) at room temperature. Thereaction was stirred at room temperature for 1 hour, and then a 2N LiOHsolution (3 mL) was added. The mixture was stirred at room temperaturefor 30 minutes, and water (10 mL) and ethyl acetate (30 mL) were added.The organic layer was separated, washed with brine, dried (sodiumsulfate) and concentrated in vacuo. The residue obtained was purified bychromatography on silica gel (hexane:ethyl acetate 1:2) to give(R)—N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide(0.21 g, 70%) as a solid.

Step B: A mixture of(R)—N-(4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide(0.21 g, 0.82 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (0.33 g,1.65 mmol) and DIEA (0.43 mL, 2.47 mmol) in n-BuOH (2 mL) was stirred at140° C. (bath) for 12 hours. The solvent was removed, and the residuewas dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine(10 mL), dried (sodium sulfate) and concentrated in vacuo. The residueobtained was purified by reverse phase chromatography (Biotage SP4, C-1825M+, 10-80% CH₃CN/water gradient, 25 CV). The product isolated wasdissolved in DCM (2 mL), and TFA (0.5 mL) was added. The mixture wasstirred at room temperature for 1 hour. The solvent was removed. Theresidue was dissolved in DCM (1 mL) and 2N HCl in ether (3 mL) wasadded. The solid formed was collected to give(R)—N-(4-((R)-3-aminopiperidin-1-yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamidehydrochloride (0.31 g, 93%) as a solid. ¹H NMR (400 MHz, D₂O) δ 8.08 (d,1H), 7.38 (s, 1H), 4.02 (m, 1H), 3.80 (m, 1H), 3.46 (m, 2H), 3.37 (s,3H), 3.30 (m, 1H), 3.20 (m, 1H), 2.07 (m, 1H), 1.76 (m, 1H), 1.62 (m,2H), 1.33 (d, 3H). LCMS (APCI+) m/z 336 (M+H)+.

Example 119

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-ethoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

Step A: sec-Butyllithium (27 mL, 38 mmol; 1.4M in cyclohexane) was addeddropwise to 4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine(5.0 g, 17 mmol; Example 1, Step D) in THF (200 mL) at −78° C., and thereaction was stirred for 30 minutes.(1S)-(+)-(10-Camphorsulfonyl)oxaziridine (9.4 g, 41 mmol) in THF (40 mL)was added rapidly, and the reaction was stirred at −78° C. for 30minutes. A solution of saturated ammonium chloride (50 mL) was added,and the reaction mixture was allowed to reach room temperature. Afterone hour, the aqueous phase was extracted with AcOEt, dried over MgSO₄and concentrated to a solid, which was triturated in ether. The solid(most of the camphor side product) was filtered off, and the filtratewas concentrated and purified by reverse phase chromatography (BiotageSP4, C-18 40M+, water/ACN 40/60->0/100, 12 CV) to yield4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (2.6 g, 49%yield) as a paste.

Step B: Potassium carbonate (3.49 g, 25.3 mmol) and bromoethane (1.10 g,10.1 mmol) were added to4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (2.6 g,8.43 mmol) in DMF (5 mL). The reaction was heated to 60° C. in a sealedtube for 24 hours and then filtered. After concentration, the filtratewas purified by reverse phase chromatography (Biotage SP4, C-18 25M+,water/ACN, 90/10->10/90, 20CV) to yield5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridine (360 mg, 12% yield) as asolid.

Step C: Cold (about 0 to about 5° C.) fuming nitric acid (10 mL) wasadded to 5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridine (340 mg, 0.944mmol). The reaction was stirred at 0° C. for 15 minutes and then ice wasadded. The resulting solid was filtered and dried to yield5-ethoxy-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (165 mg, 78% yield)as a solid.

Step D: Tin chloride (674 mg, 3.55 mmol) was added to5-ethoxy-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (160 mg, 0.711 mmol)in 6N HCl (5 mL) at about 0 to about 5° C., and then the reaction wasstirred at 0 to about 5° C. for 2 hours. The solution was neutralized byaddition of 6N NaOH and then extracted with CHCl₃/IPA (3:1). Thecombined organic phases were dried over MgSO₄ and concentrated to leave5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (120 mg, 86% yield)as a solid.

Step E: Cyclopropanecarbonyl chloride (63.1 μL, 0.676 mmol) was addeddropwise to 5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (120 mg,0.615 mmol) in pyridine (5 mL) at 0° C. The reaction was stirred atabout 0 to about 5° C. for 2 hours and then concentrated to dryness.Water (10 mL) was added and extracted with CHCl₃/IPA (3:1). The combinedorganic phases were dried over MgSO₄ and concentrated to yieldN-(5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide(90 mg, 55% yield) as a solid.

Step F: (R)-tert-Butyl piperidin-3-ylcarbamate (205 mg, 1.0 mmol) wasadded toN-(5-ethoxy-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide(90 mg, 0.34 mmol) in n-butanol (2 mL). The reaction was stirred at 160°C. for 24 hours in a sealed tube. After cooling down and concentration,the residue was purified by reverse phase chromatography (Biotage SP4,C-18 25M+, water/ACN 90/10->10/90, 30CV) to yield (R)-tert-butyl1-(3-(cyclopropanecarboxamido)-5-ethoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(39 mg) as a solid.

Step G: TFA (3 mL) was added to (R)-tert-butyl1-(3-(cyclopropanecarboxamido)-5-ethoxy-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(39 mg, 0.088 mmol), and the reaction was stirred at room temperaturefor 30 minutes. After concentration, the residue was dissolved in MeOH(0.5 mL) and added to a 2N solution of HCL in ether. The resulting solidwas collected and dried to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-ethoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (28 mg, 93% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.80 (s, 1H), 9.85 (s, 1H), 8.43 (s, 1H), 8.25 (s, 2H), 8.00 (s, 1H),7.40 (s, 1H), 4.05 (q, 2H), 3.68-3.12 (m, 4H), 2.06-1.45 (m, 5H), 1.36(t, 3H), 1.02 (t, 1H), 0.80-0.70 (m, 4H). LCMS (APCI+) m/z 344.1 (M+H)+.

Example 120

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

Step A: 4,4,5,5-Tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (436mg, 2.59 mmol), PS-tetrakis (triphenylphosphine) palladium (786 mg,0.0864 mmol, 0.10 mmol/1 g) and 2N sodium carbonate (1296 μL, 2.59 mmol)were added to (R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(500 mg, 0.864 mmol; Example 107, Step A) in degassed dioxane (1 mL).The reaction was heated to 120° C. for an hour under microwaveirradiation. The reaction was then heated to 150° C. for 30 minutes. Thereaction was filtered and extracted with DCM. The organic layer wasconcentrated, and the resulting residue was purified by reverse phasechromatography (Gilson, C-18, 5-95% CH₃CN/water) to yield (R)-tert-butyl1-(3-(cyclopropanecarboxamido)-5-(prop-1-en-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(236 mg, 62% yield).

Step B: (R)-tert-Butyl1-(3-(cyclopropanecarboxamido)-5-(prop-1-en-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(236 mg, 0.53 mmol), 2,2,2-trifluoroacetate (290 mg, 0.524 mmol) and 10%Pd/C (558 mg, 0.524 mmol) were placed in ethanol (10 mL). The reactionwas then hydrogenated at about 1 to about 2 atm (balloon) at roomtemperature for 18 hours. The reaction was filtered through a plug ofcelite and concentrated. The residue was purified by reverse phasechromatography (Gilson, C-18, 5-95% CH₃CN/water). The product was thendissolved in TFA and stirred for 15 minutes. The reaction wasconcentrated, and the resulting residue was dissolved in 10% MeOH in DCMand added to a stirred solution of 2M HCl in ether. The reaction wasconcentrated, and the resulting residue was purified by reverse phasechromatography (Gilson, C-18, 0-60% CH₃CN/water). The product was thendissolved in 10% MeOH in DCM and added to a stirred solution of 2M HClin ether. The reaction was concentrated to give(R)—N-(4-(3-aminopiperidin-1-yl)-5-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (21 mg, 10% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.07 (s, 1H), 7.32 (s, 1H), 3.57 (d, 1H), 3.39 (m, 1H), 3.30-3.05 (m,4H), 2.12 (m, 1H), 1.77 (m, 3H), 1.53 (m, 1H), 1.16 (d, 6H), 0.93-0.82(m, 4H). LCMS (APCI+) m/z 342.1 (M+H)+, Retention time=2.37 minutes(Method 3).

Example 121

(R)—N-(5-Bromo-4-(3-(2-methoxyethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (0.100 g, 0.222 mmol; Example 29, Step C),1-bromo-2-methoxyethane (0.0246 mL, 0.266 mmol), and DIEA (0.154 mL,0.887 mmol, d 0.742) were placed in DMF (2 mL) and heated to 80° C. for18 hours. The reaction was then poured into water and extracted withEtOAc. The combined organic fractions were dried (MgSO₄), filtered, andconcentrated to give the crude product, which was purified by reversephase chromatography (Biotage SP4, C-18 25M+, 20-50% CH₃CN/water). Theproduct was next dissolved in minimal DCM (with MeOH to aid solubility)and added to a stirring solution of 1M HCl in ether. The resulting solidwas filtered, washed with ether and dried to give(R)—N-(5-bromo-4-(3-(2-methoxyethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide(0.03 g, 30%). ¹H NMR (400 MHz, D₂O) δ 8.23 (s, 1H), 7.26 (s, 1H),3.77-3.74 (m, 1H), 3.54-3.50 (m, 3H), 3.28-3.11 (m, 5H), 3.18 (s, 3H),2.19-2.12 (m, 1H), 1.82-1.61 (m, 4H), 0.90-0.82 (m, 4H). LCMS (APCI+)m/z 436, 438 (M+H)+.

Example 122

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolidine-1-carboxamide

Step A: (R)-tert-Butyl piperidin-3-ylcarbamate (1619 mg, 8.08 mmol) wasadded to a mixture of 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine(500 mg, 2.69 mmol; Example 8, Step D) andN-ethyl-N-isopropylpropan-2-amine (1408 μL, 8.08 mmol) in NMP (6.75 mL).N₂ was bubbled through the mixture for 5 minutes, and the reaction wasstirred at 120° C. under N₂ for 24 hours. The mixture was allowed tocool, was diluted with 20% EtOAc/Et₂O (200 mL) and washed with water(5×50 mL). The organic layer was then dried over MgSO₄, filtered, andconcentrated in vacuo to provide the crude (R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate.LCMS (APCI+) m/z 366 (M+H)+.

Step B: Di(1H-imidazol-1-yl)methanone (2185 mg, 13.5 mmol) was added toa stirring solution of crude (R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(986 mg, 2.70 mmol) in THF (10 mL), and the mixture was stirred at roomtemperature. After 18 hours, the reaction mixture was concentrated invacuo. The residue obtained was dissolved in EtOAc (100 mL) and washedwith water (4×20 mL) and brine (1×20 mL). The organic layer wasseparated, dried (MgSO₄), filtered, and concentrated in vacuo. Theresidue obtained was purified by reverse phase chromatography (BiotageSP4, C-18 25M+, 15-85% CH₃CN/water). The product was extracted from theaqueous phase into EtOAc (3×50 mL). The combined organic layers werewashed with water (2×10 mL), dried (MgSO₄), filtered, and concentratedin vacuo to provide (R)-tert-butyl1-(5-chloro-3-(pyrrolidine-1-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(920 mg, 74% yield) as a solid. LCMS (APCI+) m/z 463.1 (M+H)+.

Step C: A solution of (R)-tert-butyl1-(5-chloro-3-(pyrrolidine-1-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(130 mg, 0.281 mmol) in neat TFA (4 mL) was stirred at room temperaturefor 10 minutes, and then the TFA was removed in vacuo. The resultingoily residue was dissolved in CH₃OH (5 mL) and evaporated from CH₃CN(2×5 mL) to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrrolidine-1-carboxamidehydrochloride (112 mg, 91% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 1.68 (br s, 1H), 8.25 (s, 3H), 8.10 (s, 1H), 7.85 (s, 1H), 7.42 (d,1H), 3.51-3.45 (m, 1H), 3.44-3.36 (m, 4H), 3.34-3.22 (m, 3H), 3.16-3.07(m, 1H), 2.09-2.01 (m, 1H), 1.90-1.87 (m, 4H), 1.80-1.72 (m, 1H),1.67-1.41 (m, 2H). LCMS (APCI+) m/z 363 (M+H)+.

Example 123

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoropropanamide

Step A: (R)-tert-Butyl1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.280 g, 0.682 mmol; Example 98, Step A), 3-fluoropropanoic acid (0.314g, 3.41 mmol), BOP-Cl (0.869 g, 3.41 mmol), and triethylamine (0.761 mL,5.46 mmol) were placed in DCM (5 mL) and stirred for 1 hour. 3M aqueousLiOH (5 mL) was then added. The reaction was stirred for 1 hour, pouredinto water, and extracted with DCM. The combined organic fractions weredried (MgSO₄), filtered, and concentrated to give the crude product,which was purified by reverse phase chromatography (Biotage SP4, C-1825M+, 5-95% CH₃CN/water) to give (R)-tert-butyl1-(5-bromo-3-(3-fluoropropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.050 g, 15% yield).

Step B: (R)-tert-Butyl1-(5-bromo-3-(3-fluoropropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(50 mg, 0.103 mmol) was placed in DCM (3 mL) at room temperature. TFA (1mL) was then added, and the reaction was stirred at room temperature for1 hour and concentrated to dryness. The residue was then purified byreverse phase chromatography (Biotage SP4, C-18 25M+, 0-50%CH₃CN/water). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirred solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give the product(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoropropanamidehydrochloride (0.018 g, 38% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.24 (s, 1H), 7.29 (s, 1H), 4.77-4.73 (m, 1H), 4.66-4.65 m, 1H),3.73-3.70 (m, 1H), 3.54-3.50 (m, 1H), 3.32-3.29 (m, 1H), 3.21-3.16 (m,2H), 2.85-2.84 (m, 1H), 2.79-2.77 (m, 1H), 2.04-2.02 (m, 1H), 1.79-1.76(m, 1H), 1.67-1.65 (m, 1H), 1.56-1.53 (m, 1H). LCMS (APCI+) m/z 384, 386(M+H)+.

Example 124

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

Step A: Triethylamine (551 μL, 3.96 mmol) was added to a suspension of(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride salt (357 mg, 0.791 mmol; Example 29, Step C) in CH₂Cl₂(15 mL) at room temperature. The resulting solution was treated withdi-tert-butyl dicarbonate (363 mg, 1.66 mmol), followed byN,N-dimethylpyridin-4-amine (9.67 mg, 0.0791 mmol) and stirred at roomtemperature. After 18 hours, the mixture was diluted with CH₂Cl₂ (100mL) and washed with water (3×20 mL). The organic phase was separated,dried (MgSO₄), filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography (Biotage, 40S+, 20% EtOAc/hexane)to provide (R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(173 mg, 38% yield) as a solid. LCMS (APCI+) m/z 578.1. 580.1 (M+H)+.

Step B: A solution of (R)-tert-butyl5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(175 mg, 0.303 mmol) in dioxane (5 mL) at room temperature was treatedwith potassium carbonate (107 mg, 0.771 mmol), Pd(PPh₃)₄ (31.5 mg,0.0272 mmol), and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (34.2mg, 0.272 mmol). N₂ was bubbled through the mixture for 5 minutes, andthe mixture was heated at reflux for 24 hours under N₂ atmosphere. Themixture was then diluted with EtOAc (20 mL) and washed with water (1×5mL). The organic layer was separated, dried (MgSO₄), filtered, andconcentrated in vacuo. The residue obtained was purified by reversephase chromatography (Biotage SP4, C-18 25M+, 40-95% CH₃CN/water, 24 CV)to provide (R)-tert-butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-5-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(86 mg, 55% yield) as a solid. LCMS (APCI+) m/z 514.1 (M+H)+.

Step C: TFA (3 mL) was added to solid (R)-tert-butyl4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(cyclopropanecarboxamido)-5-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(70 mg, 0.14 mmol), and the mixture was stirred at room temperature for30 minutes. TFA was then removed in vacuo, and the resulting oilyresidue was dissolved in MeOH (1 drop) and CH₂Cl₂ (2 mL). This solutionwas treated with 2M HCl in ether (3 mL). The precipitate formed wasconcentrated in vacuo and the residue was evaporated from CH₃CN (3×5 mL)and dried under high vacuum for 24 hours to provide(R)—N-(4-(3-aminopiperidin-1-yl)-5-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (48 mg, 91% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 12.27 (br s, 1H), 9.94 (s, 1H), 8.38 (br s, 3H), 8.09 (s, 1H), 7.43(d, 1H), 3.78-3.71 (m, 1H), 3.44-3.29 (m, 2H), 3.26-3.16 (m, 2H), 2.40(s, 3H), 2.18-2.09 (m, 1H), 1.94-1.86 (m, 1H), 1.85-1.79 (m, 1H),1.74-1.62 (m, 1H), 1.59-1.49 (m, 1H), 0.88-0.79 (m, 4H). LCMS (APCI+)m/z 314 (M+H)+.

Example 125

(R)—N-(4-((R)-3-Aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide

Step A: Triethylamine (430 mg, 0.592 mL, 4.25 mmol) was slowly added toa mixture of4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg,0.849 mmol; Example 12, Step G), (R)-2-methoxypropanoic acid (106 mg,1.02 mmol) and bis(2-oxooxazolidin-3-yl)phosphinic chloride (238 mg,0.934 mmol) in anhydrous dichloromethane (10 mL). The resulting mixturewas stirred at room temperature for 16 hours. The mixture wasconcentrated, and the residue stirred in THF (5 mL) and treated withwater (20 mL). The solid, which separated, was collected by filtrationand washed with water then dried under vacuum to yield(R)—N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide(263 mg, 96% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.49 (brs, 1H), 9.48 (s, 1H), 8.59 (s, 1H), 7.89 (d, 1H), 3.93 (q, 1H), 3.41 (s,3H), 1.36 (d, 3H).

Step B: (R)-tert-Butyl piperidin-3-ylcarbamate (456 mg, 2.28 mmol) andN,N-diispropylethylamine (294 mg, 0.396 mL, 2.28 mmol) were added to asuspension of(R)—N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide(244 mg, 0.759 mmol) in n-BuOH (3 mL). The resulting mixture was heatedin a sealed tube under a nitrogen atmosphere at 160° C. for 24 hours.The cooled mixture was diluted with water and extracted with EtOAc (3×20mL). The combined organic layer was dried over MgSO₄ and filtered, andthe filtrate was concentrated to an oil, which was purified by reversephase chromatography (Biotage SP4, C-18 25M+, 15-80% CH₃CN/water, 25CV)to give tert-butyl(R)-1-(3-((R)-2-methoxypropanamido)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(151 mg, 41%) as a solid. LCMS (APCI+) m/z 386.1, 486.1 (M+H)+,Retention time=3.85 minutes.

Step C:(R)-1-(3-((R)-2-Methoxypropanamido)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(152 mg, 0.292 mmol) was stirred in trifluoroacetic acid (3 mL) at roomtemperature for 1.5 hours. The solvent was evaporated in vacuo, and theresidue was purified by reverse phase chromatography (Biotage SP4, C-1825M+, 10-60% CH₃CN/water, 25CV). The isolated product was taken up in aminimal volume of methanol and added to a stirred solution of 2NHCl-Et₂O. The salt formed was collected by filtration, washed withacetonitrile and dried under vacuum to give(R)—N-(4-((R)-3-aminopiperidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamidehydrochloride (76 mg, 53% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.54 (s, 1H), 8.07 (s, 1H), 4.03-4.0 (m, 1H), 3.46 (s, 3H), 3.43-3.33(m, 2H), 3.14-3.06 (m, 2H), 3.05-2.96 (m, 1H), 2.22-2.12 (m, 1H),1.90-1.82 (m, 1H), 1.56-1.47 (m, 1H), 1.42 (d, 3H). LCMS (APCI+) m/z386, 387 (M+H)+, Retention time=2.30 minutes.

Example 126

(R)—N-(5-Bromo-4-(3-(2-fluoroethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (0.112 g, 0.248 mmol; Example 29, Step C),1-bromo-2-fluoroethane (0.0222 mL, 0.298 mmol) and DIEA (0.173 mL, 0.993mmol, d 0.742) were placed in DMF (2 mL) and heated to 80° C. for 36hours. The reaction was then cooled to room temperature, poured intowater, and extracted with EtOAc. The combined organic fractions weredried (MgSO₄), filtered, and concentrated to give the crude product,which was purified by reverse phase chromatography (Biotage SP4, C-1840M+, 5-50% water:ACN). The product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirring solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give(R)—N-(5-bromo-4-(3-(2-fluoroethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (0.018 g, 15% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.23 (s, 1H), 7.26 (s, 1H), 4.69-4.67 (m, 1H), 4.56-4.55 (m, 1H),3.84-3.81 (m, 1H), 3.57-3.54 (m, 1H), 3.42-3.16 (m, 5H), 2.22-2.19 (m,1H), 1.80-1.73 (m, 3H), 1.57-1.55 (m, 1H), 0.90-0.80 (m, 4H). LCMS(APCI+) m/z 424, 426 (M+H)+.

Example 127

(R)—N-(4-((R)-3-Aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide

NMP (4 mL), DIEA (2.47 g, 19.1 mmol), (R)-2-methoxypropanoic acid (1.42g, 13.7 mmol), and BOP-Cl (3.48 g, 13.7 mmol) were added to a solutionof crude (R)-tert-butyl1-(3-amino-5-chloro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(1.00 g, 2.73 mmol; Example 91, Step A) in NMP (3.3 mL). The reactionwas stirred for 30 minutes. 3M LiOH (25 mL) was then added, and thereaction was stirred at room temperature for 18 hours. Water and DCMwere added to the reaction mixture, and the layers were separated. Theorganic layer was dried, filtered, and concentrated. The resultingresidue was purified by reverse phase chromatography (Biotage SP4, C-1840M+, 5-95% water:ACN) to provide(R)—N-(4-((R)-3-aminopiperidin-1-yl)-5-chloro-1-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamidehydrochloride (655 mg, 56% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.03 (s, 1H), 7.50 (s, 1H), 3.99 (q, 1H), 3.58 (m, 1H), 3.46 (m, 1H),3.37 (s, 3H), 3.29 (m, 1H), 3.15 (m, 1H), 3.00 (m, 1H), 2.09 (m, 1H),1.80-1.60 (m, 2H), 1.51 (m, 1H), 1.34 (d, 3H). LCMS (APCI+) m/z 352.0(M+H)+, Retention time=2.28 minutes (Method 3).

Example 128

(S)—N-(4-(3-Aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (750 mg, 3.26mmol; Example 1, Step H), TEA (1363 μL, 9.78 mmol), and Ac₂O (646 μL,6.85 mmol) were placed in THF (15 mL) at room temperature and stirredfor 30 minutes. The reaction was then filtered, and the solid productwas dried to provideN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (595 mg,2.19 mmol, 67% yield).

Step B: N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide(0.190 g, 0.698 mmol), DIEA (0.365 mL, 2.10 mmol), and (S)-tert-butylpyrrolidin-3-ylcarbamate (0.390 g, 2.10 mmol) were placed in n-BuOH (2mL) and heated to 135° C. for 8 hours. The reaction was then cooled toroom temperature and concentrated to dryness. The residue was purifiedby silica gel chromatography (500:18 DCM:MeOH) to give (S)-tert-butyl1-(3-acetamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate(0.240 g, 78% yield).

Step C: (S)-tert-Butyl1-(3-acetamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate(0.250 g, 0.570 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added, and the reaction was stirred at room temperaturefor 1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-50%water:ACN). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirring solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give(S)—N-(4-(3-aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamidehydrochloride (0.21 g, 90% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.17 (s, 1H), 7.24 (s, 1H), 4.10-4.05 (m, 1H), 3.95-3.84 (m, 2H),3.79-3.70 (m, 2H), 2.37-2.32 (m, 1H), 2.07 (s, 3H), 2.02-1.96 (m, 2H).LCMS (APCI+) m/z 338, 340 (M+H)+.

Example 129

(R)—N-(4-(3-Aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxyacetamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.600 g, 2.61mmol; Example 1, Step H), 2-acetoxyacetic acid (0.647 g, 5.48 mmol),BOP-Cl (1.39 g, 5.48 mmol), and triethylamine (1.82 mL, 13.0 mmol) wereplaced in DCM (10 mL) and stirred at room temperature for 1 hour. 3Maqueous LiOH (3 mL) was then added. The reaction was stirred for 2hours, poured into water, and extracted with DCM. The combined organicfractions were dried (MgSO₄), filtered, and concentrated to give thecrude product, which was purified by reverse phase chromatography(Biotage SP4, C-18 25M+, 5-95% CH₃CN/water) to giveN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxyacetamide(0.400 g, 53% yield).

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxyacetamide(0.200 g, 0.694 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.388 g,2.08 mmol), and DIEA (0.121 mL, 0.694 mmol, d 0.742) were placed inn-BuOH and heated to 135° C. for 8 hours. The reaction was then cooledto room temperature and concentrated to dryness. The resulting residuewas purified by reverse phase chromatography (Biotage SP4, C-18 25M+,5-75% CH₃CN/water) to give the product (R)-tert-butyl1-(5-bromo-3-(2-hydroxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate(0.150 g, 48% yield).

Step C: (R)-tert-Butyl1-(5-bromo-3-(2-hydroxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate(0.150 g, 0.330 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added, and the reaction was stirred at room temperaturefor 1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-50%CH₃CN/water). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirred solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give(R)—N-(4-(3-aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxyacetamidehydrochloride (0.120 g, 85% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.17 (s, 1H), 7.46 (s, 1H), 4.13 (s, 2H), 4.01-3.93 (m, 1H0, 3.91-3.88(m, 1H), 3.68-3.61 (m, 1H), 3.60-3.53 (m, 2H), 2.41-2.38 (m, 1H),2.05-2.02 (m, 1H). LCMS (APCI+) m/z 354, 356 (M+H)+.

Example 130

(S)—N-(4-((R)-3-Aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxypropanamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.350 g, 1.52mmol; Example 1, Step H), (S)-2-acetoxypropanoic acid (0.422 g, 3.20mmol), BOP-Cl (0.813 g, 3.20 mmol), and triethylamine (1.06 mL, 7.61mmol) were placed in DCM (5 mL) and stirred for 1 hour. 3M aqueous LiOH(3 mL) was then added, and the reaction was stirred for 1 hour and thenpoured into water and extracted with DCM. The combined organic fractionswere dried (MgSO₄), filtered, and concentrated to give the crudeproduct, which was purified by reverse phase chromatography (BiotageSP4, C-18 25M+, 0-60% CH₃CN/water) to give(S)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxypropanamide(0.040 g, 9% yield).

Step B:(S)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxypropanamide(0.040 g, 0.13 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.074 g,0.40 mmol) and DIEA (0.069 mL, 0.40 mmol, d 0.742) were placed in n-BuOH(1 mL) and heated to 135° C. for 8 hours. The reaction was then cooledto room temperature and concentrated to dryness. The resulting residuewas purified by reverse phase chromatography (Biotage SP4, C-18 25M+,0-60% CH₃CN/water) to give tert-butyl(R)-1-(5-bromo-3-((S)-2-hydroxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate(0.040 g, 65% yield).

Step C: tert-Butyl(R)-1-(5-bromo-3-((S)-2-hydroxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate(0.040 g, 0.085 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added, and the reaction was stirred at room temperaturefor 1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-50%CH₃CN/water). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirring solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give(S)—N-(4-((R)-3-aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxypropanamidehydrochloride (0.022 g, 58% yield). ¹H NMR (400 MHz, D₂O) δ 8.16 (s,1H), 7.50 (s, 1H), 4.32-4.30 (q, 1H), 4.03-4.00 (m, 1H), 3.89-3.84 (m,1H), 3.66-3.63 (m, 1H), 3.59-3.55 (m, 1H), 3.48-3.46 (m, 1H), 2.42-2.39(m, 1H), 2.07-2.04 (m, 1H), 1.34-1.32 (d, 3H); LCMS (APCI+) m/z 368, 370(M+H)+.

Example 131

(R)—N-(4-(3-(Aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide

Step A: A solution of isobutyl chloride (500 mg, 0.492 mL, 4.695 mmol)in anhydrous dichloromethane (2 mL) was added dropwise to a solution of5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (900 mg, 3.912 mmol;Example 1, Step H) and triethylamine (1.78 g, 2.73 mL, 19.56 mmol) inanhydrous dichloromethane (30 mL) cooled on an ice-bath. The mixture wasstirred at ambient temperature for 1.5 hours. The mixture was evaporatedunder reduced pressure. The residue was stirred in THF (30 mL), treatedwith an aqueous 2N LiOH solution (8 mL) and stirred for 2 hours. Thesolvent was evaporated in vacuo, and the residue was stirred in water(30 mL,). The solid, which separated, was collected by filtration,washed with water and dichloromethane (10 mL) and dried under vacuum toyield N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide(778.5 mg, 66% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO) δ 12.04 (brs, 1H), 9.41 (s, 1H), 8.34 (d, 1H), 7.56 (s, 1H), 2.72-2.60 (m, 1H),1.11 (d, 6H). LCMS (APCI+) m/z 299.9 (M+)+, Retention time=2.80 minutes.

Step B: (S)-tert-Butyl pyrrolidin-3-ylmethylcarbamate (505 mg, 2.52mmol) was added to a suspension ofN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide (252 mg,0.84 mmol) and N,N-diisopropylethylamine (326 mg, 0.439 mL, 2.52 mmol)in n-BuOH (2.5 mL). The resulting mixture was heated in a sealed tubeunder nitrogen at 160° C. for 18 hours. The cooled mixture was dilutedwith water and extracted with EtOAc (3×20 mL). The combined organiclayer was dried over MgSO₄ and filtered, and the filtrate wasconcentrated to an oil and purified by reverse phase chromatography(Biotage SP4, C-18 25M+, 20-85% CH₃CN/water, 25CV) to give(R)-tert-butyl(1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)methylcarbamate(245 mg, 61% yield) as a solid. LCMS (APCI+) m/z 480.1, 482.1 (M+H)+,Retention time=3.66 minutes.

Step C: (R)-tert-Butyl(1-(5-bromo-3-isobutyramido-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-yl)methylcarbamate(245 mg, 0.510 mmol) was stirred in TFA (3 mL) at room temperature for1.5 hours. The solvent was evaporated in vacuo, and the residue purifiedby reverse phase chromatography (Biotage SP4, C-18 25M+, 2-55%CH₃CN/water, 25CV). The isolated product was taken up in a minimalvolume of methanol and added to a stirred solution of 2N HCl-Et₂O. Thesalt formed was collected by filtration, washed with acetonitrile anddried under vacuum to give(R)—N-(4-(3-(aminomethyl)pyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramidehydrochloride (128 mg, 55% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.74 (br s, 1H), 9.32 (s, 1H), 8.27 (s, 1H), 8.15 (br s, 1H), 7.63(d, 1H), 3.68-3.61 (m, 1H), 3.57-3.43 (m, 2H), 3.31-3.24 (m, 1H),3.03-2.92 (m, 2H), 2.80-2.60 (m, 2H), 2.30-2.20 (m, 1H), 1.93-1.80 (m,1H), 1.16 (d, 6H). LCMS (APCI+) m/z 380, 382.1 (M+H)+, Retentiontime=2.11 minutes.

Example 132A

(S)—N-(4-((R)-3-Aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.5 g, 2.17mmol; Example 1, Step H), (S)-2-methoxypropanamide (0.471 g, 4.56 mmol),BOP-Cl (1.16 g, 4.56 mmol), and triethylamine (1.51 mL, 10.9 mmol) wereplaced in DCM (10 mL) and stirred for 18 hours at room temperature, thenpoured into water, and extracted with DCM. The combined organicfractions were dried (MgSO₄), filtered, and concentrated to give thecrude product, which was purified by reverse phase chromatography(Biotage SP4, C-18 25M+, 5-95% CH₃CN/water) to give(S)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide(0.6 g, 87% yield).

Step B:(S)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide(0.6 g, 1.9 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.7mmol), and DIEA (0.99 mL, 5.7 mmol) were placed in n-BuOH (4 mL) andheated at 135° C. for 12 hours. The reaction was cooled to roomtemperature, concentrated, and purified by silica gel chromatography(500:15 DCM:MeOH) to give tert-butyl(R)-1-(5-bromo-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate(0.55 g, 60% yield).

Step C: tert-Butyl(R)-1-(5-bromo-3-((S)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate(0.41 g, 0.85 mmol) was placed in DCM (3 mL) at room temperature. TFA (1mL) was then added, and the reaction was stirred at room temperature for1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-50%CH₃CN/water). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirring solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give(S)—N-(4-((R)-3-aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamidehydrochloride (0.35 g, 90% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.17 (s, 1H), 7.39 (s, 1H), 4.03-3.96 (m, 3H), 3.95-3.79 (m, 1H),3.73-3.69 (m, 1H), 3.60-3.53 (m, 1H), 3.36 (s, 3H), 2.40-2.35 (m, 1H),2.07-2.02 (m, 1H), 1.31-1.29 (d, 3H). LCMS (APCI+) m/z 382, 384 (M+H)+.

Example 132B

(R)—N-(4-((R)-3-aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide

Step A: 5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.5 g, 2.17mmol; Example 1, Step H), (R)-2-methoxypropanoic acid (0.475 g, 4.56mmol), BOP-Cl (1.16 g, 4.56 mmol), and triethylamine (1.51 mL, 10.9mmol) were placed in DCM (5 mL) and stirred at room temperature for 1hour. 3M aqueous LiOH (3 mL) was then added. The reaction was stirredfor 10 minutes, then poured into water, and extracted with DCM. Thecombined organic fractions were dried (MgSO₄), filtered, andconcentrated to give the crude product, which was purified by silica gelchromatography (500:15 DCM:MeOH) to give(R)—N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide.

Step B:(R)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide(0.6 g, 1.9 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.7mmol), and DIEA (0.99 mL, 5.7 mmol, d 0.742) were place in n-BuOH (4 mL)and heated at 135° C. for 12 hours. The reaction was cooled to roomtemperature, concentrated, and purified by silica gel chromatography(500:15 DCM:MeOH) to give tert-butyl(R)-1-(5-bromo-3-((R)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate(0.56 g, 61% yield).

Step C: tert-Butyl(R)-1-(5-bromo-3-((R)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate(0.150 g, 0.311 mmol) was placed in DCM (3 mL) at room temperature. TFA(1 mL) was then added, and the reaction was stirred at room temperaturefor 1 hour and concentrated to dryness. The resulting residue was thenpurified by reverse chromatography (Biotage SP4, C-18 25M+, 0-50%CH₃CN/water). The resulting product was next dissolved in minimal DCM(with MeOH to aid solubility) and added to a stirring solution of 1M HClin ether. The resulting solid was filtered, washed with ether and driedto give(R)—N-(4-((R)-3-aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamidehydrochloride (0.110 g, 78% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ8.16 (s, 1H), 7.44 (s, 1H), 3.99-3.96 (m, 2H), 3.91-3.87 (m, 1H),3.71-3.64 (m, 2H), 3.57-3.53 (m, 1H), 3.36 (s, 3H), 2.44-2.39 (m, 1H),2.06-2.02 (m, 1H), 1.31-1.29 (d, 3H). LCMS (APCI+) m/z 382, 384 (M+H)+.

Example 133

(R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide

Step A: 5-Chloro-4-fluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (1.00 g, 4.6mmol) and platinum-0.5% Fe (0.452 g, 0.06 mmol) were suspended in THF(12.4 mL) with IPA (6.2 mL). The mixture was hydrogenated at 20 psi for20 hours, and then the catalyst was removed by filtration. The filtratewas concentrated to dryness, and5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (923 mg, 107% yield)was isolated as a solid.

Step B: N-Ethyl-N-isopropylpropan-2-amine (279 mg, 2.16 mmol) followedby cyclopentanecarbonyl chloride (143 mg, 1.08 mmol) were added dropwiseto 5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 1.08mmol) in THF (10 mL) at 0° C. The reaction mixture was stirred at 0° C.for 1 hour and then concentrated to dryness. The residue was trituratedin water and then filtered. The solid was washed with ACN and driedunder vacuum to provideN-(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide(186 mg, 61% yield) as a solid.

Step C: (R)-tert-Butyl piperidin-3-ylcarbamate (192 mg, 0.96 mmol) wasadded toN-(5-chloro-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamide(90 mg, 0.32 mmol) in s-BuOH (2 mL), and the reaction mixture was heatedto 130° C. for 30 hours in a sealed tube. After cooling down, thereaction was concentrated to dryness, dissolved in AcOEt (10 mL) andwashed with 10% aqueous citric acid and brine. The aqueous phase wasdiluted with hexanes (10 mL) and passed through a short plug of silicagel. The silica gel was rinsed with AcOEt/hexanes (1/1, 100 mL), and thecombined organic phases were concentrated in vacuo. The resulting solidwas crystallized from AcOEt to yield (R)-tert-butyl1-(5-chloro-3-(cyclopentanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(85 mg, 58% yield) as a solid.

Step D: (R)-tert-Butyl1-(5-chloro-3-(cyclopentanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(80 mg, 0.17 mmol) was stirred in 4N HCl in IPA (5 mL) at about 30-40°C. for 24 hours. The reaction was concentrated to dryness to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopentanecarboxamidehydrochloride (72 mg, 115% yield) as a solid.

Example 134

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)acetamide

Step A: 2-(Methylsulfonyl)acetic acid (601 mg, 4.35 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) andtriethylamine (1100 mg, 10.9 mmol) were added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) inDCM (100 mL). The reaction was stirred at room temperature for 1 hour,and then 2N aqueous Na₂CO₃ (50 mL) was added. The resulting suspensionwas filtered, and the solid was rinsed with DCM and water. After drying,N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)acetamide(503 mg, 66.1% yield) was obtained as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)acetamide (300 mg, 0.857 mmol) and (R)-tert-butylpiperidin-3-ylcarbamate (515 mg, 2.57 mmol) in s-BuOH (5 mL) were heatedto 135° C. in a sealed tube for 24 hours. After cooling down, theresidue was concentrated and purified by reverse phase chromatography(SP4, 25M, water/ACN 80/20->0/100, 30 CV) to yield (R)-tert-butyl1-(5-bromo-3-(2-(methylsulfonyl)acetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(306 mg, 67.3% yield) as a solid.

Step C: (R)-tert-Butyl1-(5-bromo-3-(2-(methylsulfonyl)acetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(300 mg, 0.566 mmol) was dissolved in TFA (10 mL) and stirred at roomtemperature for 1 hour. The reaction was concentrated to dryness,dissolved in MeOH (4 mL), and then added to a stirred 2N HCl in ethersolution. The resulting precipitate was filtered and dried to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)acetamidehydrochloride (98 mg, 40.3% yield) as a solid. ¹H NMR (400 MHz,(CD₃)₂SO) δ 11.95 (s, 1H), 9.87 (s, 1H), 8.18-8.26 (m, 4H), 7.50 (s,1H), 4.47 (dd, 2H), 3.43-3.35 (m, 2H), 3.23 (m, 1H), 3.14 (s, 3H), 3.02(m, 2H), 2.04 (m, 1H), 1.72 (m, 2H), 1.50 (m, 1H). LCMS (APCI+) m/z432.3 (M+2H)+.

Example 135

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methylcyclopropanecarboxamide

Step A: 1-Methylcyclopropanecarboxylic acid (435 mg, 4.35 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (553 mg, 2.17 mmol) andtriethylamine (1100 mg, 10.9 mmol) were added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) inDCM (100 mL). The reaction was stirred at room temperature for 1 hour,and then 2N aqueous Na₂CO₃ was added (50 mL). The resulting suspensionwas filtered, and the solid was rinsed with DCM and water. After drying,N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methylcyclopropanecarboxamide(464 mg, 68.4% yield) was obtained as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methylcyclopropanecarboxamide(464 mg, 1.49 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (298 mg,1.49 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for24 hours. After cooling down, the residue was concentrated and purifiedby reverse phase chromatography (SP4, 25M, water/ACN 80/20->0/100, 30CV) to yield (R)-tert-butyl1-(5-bromo-3-(1-methylcyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(382 mg, 52.2% yield) as a solid.

Step C: (R)-tert-Butyl1-(5-bromo-3-(1-methylcyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(380 mg, 0.772 mmol) was dissolved in TFA (10 mL) and stirred at roomtemperature for 1 hour. The reaction was concentrated to dryness,dissolved in MeOH (4 mL), and then added to a stirring 2N HCl in ethersolution. The resulting precipitate was filtered and dried to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methylcyclopropanecarboxamidehydrochloride (150 mg, 49.5% yield) as a solid. ¹H NMR (400 MHz,(CD₃)₂SO) δ 11.78 (s, 1H), 9.06 (s, 1H), 8.27 (br s, 2H), 8.19 (s, 1H),7.55 (s, 1H), 3.40-3.26 (m, 4H), 3.04 (m, 1H), 2.08 (m, 1H), 1.80-1.60(m, 2H), 1.46 (m, 1H), 1.42 (s, 3H), 1.06 (m, 2H), 0.63 (m, 2H). LCMS(APCI+) m/z 392.3 (M).

Example 136

trans-N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylcyclopropanecarboxamide

Step A: trans-2-Phenylcyclopropanecarboxylic acid (705 mg, 4.35 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) andtriethylamine (1100 mg, 10.9 mmol) were added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) inDCM (100 mL). The reaction was stirred at room temperature for 1 hour,and then 2N aqueous Na₂CO₃ was added (50 mL). The resulting suspensionwas filtered and the solid rinsed with DCM and water. After drying,trans-N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylcyclopropanecarboxamide(503 mg, 61.8% yield) was obtained as a solid.

Step B:trans-N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylcyclopropanecarboxamide(500 mg, 1.34 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (1338 mg,6.68 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for24 hours. After cooling down, the residue was concentrated and purifiedby reverse phase chromatography (SP4, 25M, water/ACN 80/20->0/100, 30CV) to yield tert-butyl(R)-1-(5-bromo-3-(trans-2-phenylcyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(359 mg, 48.5% yield) as a solid.

Step C: tert-Butyl(R)-1-(5-bromo-3-(trans-2-phenylcyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(350 mg, 0.631 mmol) was dissolved in TFA (10 mL) and stirred at roomtemperature for 1 hour. The reaction was concentrated to dryness,dissolved in MeOH (4 mL), and then added to a stirring 2N HCl in ethersolution. The resulting precipitate was filtered and dried to yieldtrans-N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylcyclopropanecarboxamidehydrochloride (230 mg, 80.2% yield) as a solid (mixture ofdiastereoisomers). ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.84 (d, 1H), 9.71 (d,1H), 8.25 (br s, 3H), 8.17 (s, 1H), 7.28-7.22 (m, 2H), 7.18-7.12 (m,3H), 3.50-3.30 (m, 4H), 3.20-3.00 (m, 2H), 2.35 (m, 0.5H), 2.16 (m,0.5H), 2.0-1.85 (m, 1H), 1.70-1.26 (m, 5H). LCMS (APCI+) m/z 454.4 (M).

Example 137

N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylpropanamide

Step A: 2-Phenylpropanoic acid (653 mg, 4.35 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) andtriethylamine (1100 mg, 10.9 mmol) were added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) inDCM (100 mL). The reaction was stirred at room temperature for 1 hour,and then 2N aqueous Na₂CO₃ (50 mL) was added. The resulting suspensionwas filtered, and the solid was rinsed with DCM and water. After drying,N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylpropanamide(384 mg, 48.8% yield) was obtained as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylpropanamide(170 mg, 0.469 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (282 mg,1.41 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for24 hours. After cooling down, the residue was concentrated and purifiedby reverse phase chromatography (SP4, 25M, water/ACN 80/20->0/100, 30CV) to yield tert-butyl(3R)-1-(5-bromo-3-(2-phenylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(142 mg, 55.8% yield) as a solid.

Step C: tert-Butyl(3R)-1-(5-bromo-3-(2-phenylpropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(140 mg, 0.258 mmol) was dissolved in TFA (10 mL) and stirred at roomtemperature for 1 hour. The reaction was concentrated to dryness,dissolved in MeOH (4 mL), and then added to a stirring 2N HCl in ethersolution. The resulting precipitate was filtered and dried to yieldN-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylpropanamidehydrochloride (100 mg, 87.6% yield) as a solid. ¹H NMR (400 MHz,(CD₃)₂SO) δ 11.82 (d, 1H), 9.35 (d, 1H), 8.30 (br s, 2H), 8.22 (d, 1H),7.63 (d, 1H), 7.44-7.25 (m, 5H), 4.03-3.90 (m, 1H), 3.45-2.75 (m, 6H),2.09-1.94 (m, 1H), 1.70-1.35 (m, 3H), 1.45 (dd, 3H). LCMS (APCI+) m/z442.4 (M).

Example 138

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylacetamide

Step A: 2-Phenylacetic acid (592 mg, 4.35 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) andtriethylamine (1100 mg, 10.9 mmol) were added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) inDCM (100 mL). The reaction mixture was stirred at room temperature for 1hour, and then 2N aqueous Na₂CO₃ (50 mL) was added. The resultingsuspension was filtered, and the solid was rinsed with DCM and water.After drying,N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylacetamide(606 mg, 80.1% yield) was obtained as a solid.

Step B:N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylacetamide(300 mg, 0.86 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (518 mg,2.58 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for24 hours. After cooling down, the residue was concentrated and purifiedby reverse phase chromatography (SP4, 25M, water/ACN 80/20->0/100, 30CV) to yield (R)-tert-butyl1-(5-bromo-3-(2-phenylacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(320 mg, 70% yield) as a solid.

Step C: (R)-tert-Butyl1-(5-bromo-3-(2-phenylacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(310 mg, 0.587 mmol) was dissolved in TFA (10 mL) and stirred at roomtemperature for 1 hour. The reaction was concentrated to dryness,dissolved in MeOH (4 mL), and then added to a stirring 2N HCl in ethersolution. The resulting precipitate was filtered and dried to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylacetamidehydrochloride (280 mg. 111% yield) as a solid. ¹H NMR (400 MHz,(CD₃)₂SO) δ 11.82 (s, 1H), 9.47 (s, 1H), 8.30-8.20 (m, 3H), 7.58 (s,1H), 7.40-7.34 (m, 4H), 7.30-7.25 (m, 1H), 3.77 (s, 2H), 3.46-3.18 (m,4H), 3.00 (d, 1H), 2.05 (d, 1H), 1.72 (m, 1H), 1.58-1.38 (m, 2H). LCMS(APCI+) m/z 428.4 (M).

Example 139

(S)—N-(4-(3-aminoazepan-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

Step A: (S)-tert-Butyl azepan-3-ylcarbamate (431 mg, 2.01 mmol;commercially available or Moon, Sung-Hwan, et al. “An EfficientConversion of Chiral α-Amino Acids to Enantiomerically Pure 3-AminoCyclic Amines.” Synthetic Communications. Vol. 28, No. 21 (1998): pp.3919-3926) was added toN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide(200 mg, 0.671 mmol) in n-BuOH (3 mL), and the reaction was heated for18 hours to 160° C. in a sealed tube. After concentration, the residuewas purified by chromatography (SP4, 25M, water/ACN 100/0->0/100, 40CV)to yield (S)-tert-butyl1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)azepan-3-ylcarbamate(30 mg, 9% yield) as a solid.

Step B: (S)-tert-Butyl1-(5-bromo-3-(cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)azepan-3-ylcarbamate(30 mg, 0.061 mmol) was stirred in TFA (5 mL) for 1 hour. Afterconcentration, the residue was dissolved in a minimal amount of methanoland then added dropwise to a 2N HCl solution in ether. The resultingsolid was collected and dried to yield(S)—N-(4-(3-aminoazepan-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (16 mg, 67% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 12.09 (s, 1H), 10.12 (s, 1H), 9.48 (br s, 2H), 8.25 (s, 1H), 7.32 (d,1H), 3.30-3.00 (m, 4H), 2.09-1.55 (m, 8H), 0.90-0.75 (m, 4H). LCMS(APCI+) m/z 392.0 (M).

Example 140

(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)azetidine-1-carboxamide

Step A: Di(1H-imidazol-1-yl)methanone (3.2 g, 19 mmol) was added to(R)-tert-butyl1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(2.0 g, 4.9 mmol; Example 98, Step A) in THF (100 mL), and the reactionmixture was stirred at room temperature for 18 hours. The reactionsolution was used as is. Azetidine (113 mg, 1.98 mmol) was added to(R)-tert-butyl1-(5-bromo-3-(1H-imidazole-1-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(200 mg, 0.397 mmol) in THF (20 mL), and the reaction was stirred for 18hours. The reaction was concentrated to dryness and then purified byreverse phase chromatography (SP4, 25M, water/ACN 90/10->0/100, 30 CV)to yield (R)-tert-butyl1-(3-(azetidine-1-carboxamido)-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(90 mg, 46.0% yield) as a solid.

Step B: (R)-tert-Butyl1-(3-(azetidine-1-carboxamido)-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(74 mg, 0.15 mmol) was dissolved in TFA (3 mL) and stirred at roomtemperature for 1 hour. After concentration, the residue was dissolvedin MeOH (1 mL) and added dropwise to a 2N HCl in ether solution. Theresulting solid was filtered and dried to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)azetidine-1-carboxamidehydrochloride (43 mg, 73% yield) as a solid. ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.84 (s, 1H), 8.30 (s, 2H), 8.23 (s, 1H), 7.74 (s, 1H), 7.40 (d, 1H),3.66 (dd, 2H), 3.54-3.42 (m, 2H), 3.26-3.10 (m, 5H), 2.10-2.04 (m, 1H),1.90-1.72 (m, 4H), 1.52 (br s, III). LCMS (APCI+) m/z 394.4 (M+H).

Example 141

N-(4-((R)-3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylcyclopropanecarboxamide

Step A: 2,2-Dimethylcyclopropanecarboxylic acid (0.992 g, 8.69 mmol),bis(2-oxooxazolidin-3-yl)phosphinic chloride (2.21 g, 8.69 mmol) andtriethylamine (2.20 g, 21.7 mmol) were added to5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (1 g, 4.35 mmol) inDCM (100 mL). The reaction was stirred at room temperature for 1 hour,and then 2N aqueous Na₂CO₃ was added. The mixture was filtered, and thesolid rinsed with water and dried to yieldN-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylcyclopropanecarboxamide(672 mg, 47.4% yield) as a solid.

Step B:N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylcyclopropanecarboxamide(500 mg, 1.53 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (921 mg,4.60 mmol) in s-BuOH (10 mL) were stirred at 130° C. for 18 hours. Thereaction was concentrated and purified by reverse phase chromatography(SP4, 25M, water/ACN 90/10->0/100, 30 CV) to yield tert-butyl(1R)-3-(5-bromo-3-(2,2-dimethylcyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)cyclohexylcarbamate(360 mg, 46.5% yield) as a solid.

Step C: tert-Butyl(1R)-3-(5-bromo-3-(2,2-dimethylcyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)cyclohexylcarbamate(341 mg, 0.675 mmol) was dissolved in TFA (5 mL) and stirred at roomtemperature for 1 hour. After concentration, the residue was dissolvedin MeOH (2 mL) and added dropwise to a 2N HCl in ether solution. Theresulting solid was filtered and dried to yieldN-(4-((3R)-3-aminocyclohexyl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylcyclopropanecarboxamidehydrochloride (237 mg, 86.7% yield) as a solid (mixture 1/1diastereoisomers). ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.78 (s, 0.5H), 11.73(s, 0.5H), 9.48 (s, 0.5H), 9.41 (s, 0.5H), 8.36-8.26 (m, 3H), 8.18 (s,0.5H), 8.17 (s, 0.5H), 7.48 (s, 0.5H), 7.44 (s, 0.5H), 3.55-3.0 (m, 6H),2.12-2.04 (m, 1H), 1.84-1.40 (m, 4H), 1.14-1.08 (m, 6H), 0.96 (m, 1H),0.90 (s, 1H). LCMS (APCI+) m/z 406.4 (M+H).

Example 142

(R)—N-(4-(3-aminopiperidin-1-yl)-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide

Step A: 1-Bromo-2-methoxyethane (0.586 g, 4.21 mmol) and potassiumcarbonate (1.16 g, 8.43 mmol) to4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-ol (1.3 g,4.21 mmol; Example 119, Step A) in DMF (13 mL). The reaction was heatedto 65° C. in a sealed tube for 18 hours, cooled down and then filtered.The filtrate was concentrated and purified by reverse chromatography(SP4, 25M, water/ACN 90/10->0/100, 30CV) to yield4-fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridine (440 mg, 49.7%yield) as an oil.

Step B: 4-Fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridine (440 mg,2.09 mmol) was added to HNO₃ fuming (4 mL) at 0-5° C., and the reactionwas stirred for 15 minutes. Ice was added, and the resulting solid wasfiltered and dried to yield4-fluoro-5-(2-methoxyethoxy)-3-nitro-1H-pyrrolo[2,3-b]pyridine (360 mg,67% yield) as a solid.

Step C: SnCl₂ (1337 mg, 7.05 mmol) was added to4-fluoro-5-(2-methoxyethoxy)-3-nitro-1H-pyrrolo[2,3-b]pyridine (360 mg,1.41 mmol) in 6N HCl (10 mL) at 0-5° C., and the reaction was stirred at0-5° C. for 1 hour. The solution was neutralized by addition of 6N NaOHand then extracted with CHCl₃/IPA 3/1. The combined organic phases weredried over MgSO₄ and concentrated to leave4-fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-3-amine (300 mg,95% yield) as an oil.

Step D: (R)-tert-Butyl piperidin-3-ylcarbamate (307 mg, 1.53 mmol) wasadded toN-(4-fluoro-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide(150 mg, 0.511 mmol) in s-BuOH (3 mL), and the reaction was stirred at150° C. for 24 hours in a sealed tube. After cooling down andconcentration, the residue was purified by reverse phase chromatography(SP4, 25M, water/ACN 90/10->0/100, 30 CV) to yield (R)-tert-butyl1-(3-(cyclopropanecarboxamido)-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(113 mg, 46.7% yield) as a solid.

Step E: (R)-tert-Butyl1-(3-(cyclopropanecarboxamido)-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate(0.110 g, 0.232 mmol) was dissolved in 5N HCl (2.32 mL, 11.6 mmol) inIPA and stirred at room temperature for 2 hours. The reaction wasconcentrated to dryness, suspended in acetonitrile (5 mL) and stirred atroom temperature for 30 minutes. The resulting precipitate was filteredand dried to yield(R)—N-(4-(3-aminopiperidin-1-yl)-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamidehydrochloride (0.094 g, 90.7% yield) as a solid. ¹H NMR (400 MHz, D₂O) δ7.82 (s, 1H), 7.21 (s, 1H), 4.13 (m, 2H), 3.75-3.81 (m, 3H), 3.47 (m,2H), 3.30 (s, 3H), 3.22 (m, 2H), 2.07 (m, 1H), 1.74 (m, 2H), 1.57-1.65(m, 2H), 0.88 (m, 2H), 0.93 (m 2H). LCMS (APCI+) m/z 374.2 (M+H).

Examples 143-184 shown in Table 1 can also be made according to theabove described methods.

TABLE 1 Ex # Structure Name NMR/LCMS 143

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5- methylpyrazine-2-carboxamide ¹H NMR (400 MHz, D₂O) δ8.81 (s, 1H), 8.44 (s, 1H), 8.05 (d, 1H), 7.57 (s, 1H), 3.68-3.65 (m,1H), 3.50-3.45 (m, 1H), 3.35-3.32 (m, 1H), 3.21-3.17 (m, 1H), 3.12-3.08(m, 1H), 2.47 (s, 3H), 2.01-1.99 (m, 1H), 1.67-1.65 (m, 2H), 1.49-1.47(m, 1H); LCMS (APCI+) m/z 370 (M + H)+ 144

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-fluoro-2- mcthylpropanamide ¹H NMR (400 MHz, (CD₃)₂SO)δ 11.85 (br s, 1H), 9.99 (s, 1H), 8.31 (br s, 2H), 8.29 (s, 1H), 7.91(s, 1H), 3.70-3.45 (m, 2H), 3.35-3.26 (m, 2H), 3.10-3.0 (m, 1H),2.16-2.08 (m, 1H), 1.92-1.72 (m, 2H), 1.67 (d, 3H), 1.61 (d, 3H),1.56-1.40 (m, 1H); LCMS (APCI+) m/z 400 (M + 2H)+, Retention time = 2.26minutes 145

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methyl-1H- pyrazole-4-carboxamide ¹H NMR (400 MHz,D₂O) δ 8.29 (s, 1H), 8.09 (s, 1H), 7.93 (s, 1H), 7.34 (s, 1H), 3.85-3.83(m, 1H), 3.81 (s, 3H), 3.50-3.43 (m, 2H), 3.15-3.12 (m, 2H), 1.96-1.93(m, 1H), 1.69-1.57 (m, 2H), 1.38-1.35 (m, 1H); LCMS (APCI+) m/z 418, 420(M + H)+ 146

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- methylbutanamide ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.74(s, 1H), 9.22 (s, 1H), 8.29-8.11 (m, 4H), 7.58 (s, 1H), 3.45-3.17 (m,5H), 3.07-2.92 (m, 1H), 2.10-1.92 (m, 1H), 1.86-1.24 (m, 5H), 1.08 (m,3H), 0.85 (m, 3H); LCMS (APCI+) m/z 394, 396 (M + H)+ 147

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- isopropoxyacetamide ¹H NMR (400 MHz, (CD₃)₂SO) δ11.81 (s, 1H), 9.38 (s, 1H), 8.28 (br s, 3H), 8.26 (s, 1H), 7.95 (br s,1H), 4.12 (s, 2H), 3.84- 3.77 (m, 1H), 3.64-3.55 (m, 1H), 3.53-3.45 (m,1H), 3.42-3.34 (m, 1H), 3.31-3.26 (m, 1H), 3.05-2.99 (m, 1H), 2.18-2.12(m, 1H), 1.93-1.84 (m, 2H), 1.55-1.45 (m, 1H), 1.24 (dd, 6H); LCMS(APCI+) m/z 410, 412 (M + H)+ 148

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-(6-methylpyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-3- yl)nicotinamide ¹H NMR (400 MHz, D₂O) δ 9.15(s, 1H), 8.80 (d, 1H), 8.71 (d, 1H), 8.66 (s, 1H), 8.40 (d, 1H), 7.98(s, 1H), 7.88 (m, 2H), 7.52 (s, 1H), 3.34 (d, 1H), 3.24 (d, 1H), 2.87(m, 1H), 2.78 (m, 1H), 2.71 (s, 3H), 2.54 (t, 1H), 1.74 (m, 1H), 1.39(m, 1H), 1.08 (m, 2H); LCMS (APCI+) m/z 428.2 (M + H)+, Retention time =1.94 minutes (Method 3) 149

(R)-N-(5-Bromo-4-(3- (methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)- 3-methoxypropanamide ¹H NMR (400 MHz,(CD₃)₂SO) δ □11.81 (s, 1H), 9.34 (br s, 1H), 9.13-9.05 (m, 2H), 8.23 (s,1H), 7.56 (br s, 1H), 3.65 (t, 2H), 3.54-3.46 (m, 2H), 3.33-3.29 (m,2H), 3.27 (s, 3H), 3.09-3.04 (m, 1H), 2.65-2.60 (m, 2H), 2.57 (t, 4H),2.26-2.22 (m, 1H), 1.91- 1.82 (m, 1H), 1.74-1.67 (m, 1H), 1.55-1.44 m,1H); LCMS (APCI+) m/z 410, 412 (M + H)+ 150

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-methyloxetane- 3-carboxamide LCMS (APCI+) m/z 408, 410(M + H)+ 151

(R)-N-(5-Bromo-4-(3- (methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3- yl)pyrimidine-2-carboxamide ¹H NMR (400 MHz,D₂O) δ 8.66 (br s, 2H), 8.07 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H),3.56-3.43 (m, 3H), 3.40-3.26 (m, 1H), 2.90-2.77 (m, 1H), 2.57 (s, 3H),2.28-2.15 (m, 1H), 1.94-1.79 (m, 1H), 1.75-1.60 (m, 1H), 1.50-1.33 (m,1H); LCMS (APCI+) m/z 430.1, 432.1 (M + H)+, Retention time = 2.11minutes 152

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5- ethylpyrimidine-2-carboxamide ¹H NMR (400 MHz, D₂O) δ8.63 (s, 2H), 8.25 (s, 1H), 7.90 (s, 1H), 3.65-3.40 (m, 3H), 2.68-2.59(m, 2H), 1.98-1.95 (m, 1H), 1.89-1.80 (m, 1H), 1.80-1.73 (m, 2H),1.61-1.50 (m, 1H), 1.22-1.13 (m, 3H); LCMS (APCI+) m/z 444.1 (M)+,Retention time = 2.30 minutes 153

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- fluoro-2-methylpropanamide ¹H NMR (400MHz, D₂O) δ 8.56 (s, 1H), 7.94 (s, 1H), 3.45-3.31 (m, 2H), 3.15-2.98 (m,3H), 2.18-2.10 (m, 1H), 1.94-1.76 (m, 2H), 1.70 (3, 3H), 1.64 (s, 3H),1.60-1.45 (m, 1H); LCMS (APCI+) m/z 388.1, 389.1 (M + H)+, Retentiontime = 2.25 minutes 154

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3- yl)isobutyramide ¹H NMR (400 MHz, (CD₃)₂SO) δ12.24 (br s, 1H), 9.25 (s, 1H), 8.48 (s, 1H), 8.29 (br s, 2H), 7.61 (d,1H), 6.20-5.76 (m, 2H), 3.05-2.80 (m, 3H), 2.15-2.05 (m, 1H), 1.85-1.74(m, 1H), 1.73-1.58 (m, 1H), 1.57-1.43 (m, 1H), 1.16 (dd, 6H); LCMS(APCI+) m/z 370.1, 371.1 (M + H)+, Retention time = 2.02 minutes 155

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- cyclopropylacetamide ¹H NMR (400 MHz,(CD₃)₂SO) δ 12.06 (br s, 1H), 9.07 (s, 1H), 8.25 (s, 1H), 8.13 (br s,2H), 7.36 (d, 1H), 3.05-3.00 (m, 3H), 2.86-2.75 (m, 1H), 2.73-2.65 (m,1H), 2.26-2.10 (m, 2H), 1.95-1.85 (m, 1H), 1.62-1.50 (m, 1H), 1.48-1.35(m, 1H), 1.34-1.20 (m, 1H), 0.94-0.84 (m, 1H), 0.34-0.25 (m, 2H),0.05-0.01 (m, 2H); LCMS (APCI+) m/z 382.1 (M + H)+, Retention time =2.13 minutes 156

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-(methylthio)-1H-pyrrolo[2,3-b]pyridin-3- yl)isobutyramide ¹H NMR (400 MHz, D₂O) δ 8.10(s, 1H), 7.27 (s, 1H), 3.93 (d, 1H), 3.67 (m, 1H), 3.43 (d, 1H), 3.16(m, 2H), 2.66 (m, 1H), 2.34 (s, 3H), 2.10 (m, 1H), 3.83 (m, 1H), 1.60(m, 2H), 1.10 (m, 6H); LCMS (APCI+) m/z 348.1 (M + H)+, Retention time =1.99 minutes (Method 3) 157

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- hydroxyacetamide ¹H NMR (400 MHz, D₂O) δ 8.14 (s,1H), 7.41 (s, 1H), 4.18 (s, 2H), 3.81-.377 (m, 1H), 3.53-3.49 (m, 1H),3.41-3.38 (m, 1H), 3.25-3.15 (m, 3H), 3.19 (s, 3H), 2.11-2.08 (m, 1H),1.77-1.68 (m, 2H) 1.56-1.52 (m, 1H); LCMS (APCI+) m/z 324 (M + H)+ 158

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- ethoxyacetamide ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.80(d, 1H), 9.66 (s, 1H), 8.36 (br s, 3H), 8.26 (s, 1H), 7.94 (d, 1H), 4.12(d, 2H), 3.74- 3.66 (m, 2H), 3.63-3.58 (m, 1H), 3.53-3.46 (m, 1H),3.43-3.36 (m, 1H), 3.33-3.26 (m, 1H), 3.02-2.96 (m, 1H), 2.20-2.13 (m,1H), 1.91-1.85 (m, 2H), 1.56-1.45 (m, 1H), 1.25 (t, 3H); LCMS (APCI+)m/z 396, 398 (M + H)+ 159

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- isopropoxyacetamide ¹H NMR (400 MHz, (CD₃)₂SO) δ11.81 (d, 1H), 9.38 (s, 1H), 8.34 (br s, 3H), 8.16 (s, 1H), 7.95 (br s,1H), 4.12 (s, 2H), 3.81 (m, 1H), 3.52-3.46 (m, 1H), 3.39-3.33 (m, 3H),3.08-3.03 (m, 1H), 2.18-2.11 (m, 1H), 1.92-1.83 (m, 2H), 1.57-1.48 (m,1H), 1.23 (dd, 6H); LCMS (APCI+) m/z 366.1 (M + H)+ 160

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- ethoxyacetamide ¹H NMR (400 MHz, (CD₃)₂SO) δ 11.79(d, 1H), 9.65 (s, 1H), 8.35 (br s, 3H), 8.17 (s, 1H), 7.95 (d, 1H),4.16-4.07 (m, 2H), 3.75-3.67 (m, 2H), 3.53-3.47 (m, 1H), 3.40-3.32 (m,3H), 3.05-3.01 (m, 1H), 2.19-2.13 (m, 1H), 1.93-1.83 (m, 2H), 1.57-1.45(m, 1H), 1.25 (t, 3H); LCMS (APCI+) m/z 352.1(M + H)+ 161

(R)-N-(5-Bromo-4-(3- (methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)- 2-isopropoxyacetamide ¹H NMR (400 MHz,(CD₃)₂SO) δ 11.81 (s, 1H), 9.33 (br s, 1H), 8.93-8.83 (m, 1H), 8.61 (brs, 1H), 8.26 (s, 1H), 7.97-7.92 (m, 1H), 4.17-4.08 (m, 2H), 3.83-3.77(m, 1H), 3.63-3.40 (m, 3H), 3.33-3.23 (m, 1H), 3.08-2.98 (m, 1H), 2.61(t, 3H), 2.28-2.20 (m, 1H), 1.95-1.84 (m, 2H), 1.52-1.41 (m, 1H), 1.23(dd, 6H); LCMS (APCI+) m/z 424.1, 426.1 (M + H)+ 162

N-(5-Bromo-4-((R)-3- (methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)- 2-isopropoxypropanamide ¹H NMR (400 MHz,(CD₃)₂SO) δ 11.80 (s, 1H), 9.36-9.31 (m, 1H), 9.13 (br s, 1H), 8.26 (s,1H), 7.93 (br s, 1H), 4.73-4.57 (m, 1H), 4.15-4.11 (m, 1H), 3.85-3.78(m, 1H), 3.55-3.46 (m, 1H), 3.387-3.19 (m, 2H), 3.09-3.01 (m, 1H),2.59-2.54 (m, 3H), 2.31-2.23 (m, 1H), 2.01-1.84 (m, 2H), 1.55-1.46 (m,1H), 1.37 (dd, 3H), 1.20 (dd, 6H); LCMS (APCI+) m/z 440.2 (M + H)+ 163

(R)-N-(5-Bromo-4-(3- (methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)- 2-ethoxyacetamide ¹H NMR (400 MHz,(CD₃)₂SO) δ 11.79 (s, 1H), 9.62 (s, 1H), 9.33 (br s, 1H), 9.16- 9.06 (m,1H), 8.26 (s, 1H), 7.94 (s, 1H), 4.12 (s, 2H), 3.74-3.66 (m, 2H),3.64-3.58 (m, 1H), 3.54-3.43 (m, 2H), 3.32-3.22 (m, 1H), 3.05-2.97 (m,1H), 2.59-2.54 (m, 3H), 2.33-2.26 (m, 1H), 1.94-1.85 (m, 2H), 1.57-1.45(m, 1H), 1.24 (t, 3H); LCMS (APCI+) m/z 410.1, 432.1 (M + H)+ 164

(R)-N-(4-((R)-3-Aminopiperidin- 1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- methoxypropanamide ¹H NMR (400 MHz, D₂O) δ 8.18 (s,1H), 7.51 (s, 1H), 4.00 (q, 1H), 3.53 (m, 2H), 3.38 (s, 3H), 3.35 (m,1H), 3.24 (m, 1H), 3.01 (m, 1H), 2.08 (m, 1H), 1.83-1.64 (m, 2H), 1.53(m, 1H), 1.35 (d, 3H); LCMS (APCI+) m/z 398.0 (M + H)+, Retention time =2.26 minutes (Method 3) 165

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- hydroxy-2-methylpropanamide ¹H NMR (400MHz, (CD₃)₂SO) δ 12.04 (br s, 1H), 8.52 (s, 1H), 8.29 (br s, 2H), 8.11(d, 1H), 3.81-3.49 (m, 1H), 3.42-3.31 (m, 1H), 3.16-3.0 (m, 3H),2.19-2.08 (m, 2H), 1.85-1.75 (m, 1H), 1.59-1.47 (m, 1H), 1.45-1.38 (m,7H); LCMS (APCI+) m/z 386.1, 387.1 (M + H)+, Retention time = 2.14minutes 166

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- isopropoxyacetamide ¹H NMR (400 MHz,(CD₃)₂SO) δ 12.19 (br s, 1H), 9.13 (s, 1H), 8.51 (s, 1H), 8.25 (br s,2H), 7.89 (s, 1H), 4.25-4.10 (m, 2H), 3.84-3.75 (m, 1H), 3.44-3.26 (m,2H), 3.13-2.96 (m, 3H), 2.18-2.10 (m, 1H), 1.90-1.76 (m, 2H), 1.58-1.40(m, 1H), 1.23 (d, 3H), 1.21 (d, 3H): LCMS (APCI+) m/z 400.1 (M + H)+,Retention time = 2.32 minutes 167

(R)-N-(5-Bromo-4-(3- (methylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)- 1-methyl-6-oxo-1,6- dihydropyridazine-3-carboxamide ¹H NMR (400 MHz, D₂O) δ 8.22 (s, 1H), 7.86 (d, 1H), 7.51 (s,1H), 7.00 (d, 1H), 3.74 (s, 3H), 3.72 (m, 1H), 3.51 (s, 3H), 3.27 (m,3H), 2.24 (m, 1H), 2.10 (m, 1H), 1.70 (m, 2H), 1.41 (m, 1H). LCMS(APCI+) m/z 460 (M + H)+ 168

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-isopropyl-6- oxo-1,6-dihydropyridazine-3- carboxamide¹H NMR (400 MHz, D₂O) δ 8.27 (s, 1H), 7.90 (d, 1H), 7.39 (s, 1H), 7.05(d, 1H), 5.15 (m, 1H), 3.70 (m, 1H), 3.41 (m, 1H), 3.31 (m, 1H),3.14-3.24 (m, 2H), 1.90 (m, 1H), 1.70 (m, 1H), 1.55 (m, 1H), 1.37 (m,1H), 1.32 (d, 6H); LCMS (APCI+) m/z 474 (M + H)+ 169A

(S)-N-(4-((R)-3-Aminopiperidin- 1-yl)-5-(methylthio)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- methoxypropanamide ¹H NMR (400 MHz, D₂O)δ 8.12 (s, 1H), 7.40 (s, 1H), 4.04 (q, 1H), 3.83 (d, 1H), 3.64 (m, 1H),3.37 (s, 3H), 3.35 (m, 1H), 3.22 (m, 2H), 2.35 (s, 3H), 2.11 (m, 1H),1.82 (m, 1H), 1.72-1.50 (m, 2H), 1.34 (d, 3H); LCMS (APCI+) m/z 398.0(M + H)+, Retention time = 2.08 minutes (Method 3) 169B

(R)-N-(4-((R)-3-Aminopiperidin- 1-yl)-5-(methylthio)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- methoxypropanamide ¹H NMR (400 MHz, D₂O)δ 8.13 (s, 1H), 7.38 (s, 1H), 4.01 (q, 1H), 3.92 (d, 1H), 3.68 (m, 1H),3.39 (m, 4H), 3.21 (m, 1H), 2.35 (s, 3H), 2.10 (m, 1H), 1.83 (m, 1H),1.70-1.50 (m, 2H), 1.37 (d, 3H); LCMS (APCI+) m/z 364.1 (M + H)+,Retention time = 2.26 minutes (Method 3) 170

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-1- (cyclopropylmethyl)-6-oxo-1,6- dihydropyridazine-3-carboxamide ¹H NMR (400 MHz, D₂O) δ 7.94 (s, 1H), 7.62 (d, 1H), 7.18 (s,1H), 6.75 (d, 1H), 3.80 (m, 1H), 3.63 (m, 1H), 3.34 (m, 1H), 3.14 (m,1H), 2.93 (m, 3H), 1.68 (m, 1H), 1.42 (m, 1H), 1.34 (m, 1H), 1.11 (m,1H), 0.94 (m, 1H), 0.14 (m, 2H), 0.01 (m, 2H); LCMS (APCI+) m/z 486 (M +H)+ 171

(R)-N-(5-Bromo-4-(3- (ethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide ¹H NMR (400 MHz,D₂O) δ 8.25 (s, 1H), 7.27 (s, 1H), 3.88-3.81 (m, 1H), 3.54-3.45 (m, 1H),3.42-3.34 (m, 1H), 3.24-3.14 (m, 2H), 3.04-2.98 (m, 2H), 2.21-2.14 (m,1H), 1.81-1.67 (m, 3H), 1.59-1.48 (m, 1H), 1.14 (t, 3H), 0.91-0.82 (m,4H); LCMS (APCI+) m/z 406.1, 408 (M + H)+ 172

(R)-N-(5-Bromo-4-(3- (ethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3- yl)isobutyramide ¹H NMR (400 MHz, D₂O) δ 8.25(s, 1H), 7.28 (s, 1H), 3.91-3.84 (m, 1H), 3.57-3.51 (m, 1H), 3.39-3.32(m, 1H), 3.20-3.12 (m, 2H), 3.02 (q, 2H), 2.69-2.62 (m, 1H), 2.20- 2.12(m, 1H), 1.82-1.77 (m, 1H), 1.70-1.46 (m, 2H), 1.16-1.09 (m, 9H); LCMS(APCI+) m/z 408.1, 410.1 (M + H)+ 173

(R)-N-(5-Bromo-4-(3- (ethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- cyclopropylacetamide ¹H NMR (400 MHz,D₂O) δ 11.82 (s, 1H), 9.25 (s, 1H), 9.06 (br s, 2H), 8.24 (s, 1H), 7.55(br s, 1H), 3.57-3.45 (m, 2H), 3.35- 3.25 (m, 2H), 3.12-3.05 (m, 1H),3.03-2.97 (m, 2H), 2.33 (d, 2H), 2.29-2.24 (m, 1H), 1.90-1.81 (m, 1H),1.71-1.61 (m, 1H), 1.58-1.46 (m, 1H), 1.22 (t, 3H), 1.13-1.06 (m, 1H),0.57-0.50 (m, 2H), 0.25-0.21 (m, 2H); LCMS (APCI+) m/z 420.1, 422 (M +H)+ 174

N-(4-((R)-3-Aminopiperidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-oxopyrrolidine 2-carboxamide ¹H NMR (400 MHz, D₂O) δ8.24 (dd, 1H), 7.39 (dd, 1H), 4.49-4.41 (m, 1H), 3.82-3.70 (m, 1H),3.63-3.52 (m, 1H), 3.34-3.24 (m, 2H), 3.23-3.11 (m, 2H), 2.62-2.50 (m,1H), 2.41-2.34 (m, 2H), 2.17-2.04 (m, 2H), 1.85-1.76 (m, 1H) 1.70- 1.48(m, 2H); LCMS (APCI+) m/z 421 (M + H)+, Retention time = 2.38 minutes175

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,3,3- trifluoropropanamide ¹H NMR (400 MHz, (CD₃)₂SO) δ11.82 (s, 1H), 8.69 (s, 1H), 8.31 (br s, 2H), 8.21 (s, 1H), 7.39 (s,1H), 4.06 (br s, 2H), 3.65- 3.00 (m, 5H), 2.19-2.10 (m, 1H), 1.90- 1.29(m, 3H); LCMS (APCI+) m/z 420 (M)+, Retention time = 2.47 minutes 176

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-isopropyl-1H-pyrrolo[2,3-b]pyridin-3-yl)propionamide ¹H NMR (400 MHz, D₂O) δ 8.08 (s, 1H), 7.33(s, 1H), 3.51 (m, 1H), 3.36 (m, 1H), 3.32 (m, 2H), 3.08 (m, 2H), 2.42(q, 2H), 2.11 (m, 1H), 1.82-1.63 (m, 2H), 1.51 (m, 1H), 1.16 (dd, 6H),1.09 (t, 3H); LCMS (APCI+) m/z 330.1 (M + H)+, Retention time = 2.25minutes (Method 3) 177

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-(ethylthio)-1H-pyrroIo[2,3-b]pyridin-3- yl)cyclopropanecarboxamide ¹H NMR (400 MHz, D₂O) δ 8.17 (s,1H), 7.26 (s, 1H), 3.89 (d, 1H), 3.64 (m, 1H), 3.47 (m, 1H), 3.20 (m,2H), 2.74 (q, 2H), 2.12 (m, 1H), 1.84-1.64 (m, 3H), 1.57 (m, 1H), 1.04(t, 3H), 0.93-0.80 (m, 4H); LCMS (APCI+) m/z 360.0 (M + H)+, Retentiontime = 2.21 minutes (Method 3) 178

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide ¹H NMR (400 MHz, D₂O) δ 8.08 (d, 1H), 7.28(s, 1H), 3.90-3.83 (m, 1H), 3.59-3.52 (m, 1H), 3.48-3.39 (m, 1H),3.36-3.20 (m, 2H), 2.68-2.60 (m, 1H), 2.11-1.99 (m, 1H), 1.80-1.68 (m,1H), 1.67-1.55 (m, 1H), 1.11-1.06 (m, 6H); LCMS (APCI+) m/z 320.1, 321.1(M + H)+, Retention time = 2.11 minutes 179

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-fluoro-1H-pyrrolo[2,3- b]pyridin-3-yl)cyclopropanecarboxamide ¹H NMR (400 MHz, D₂O) δ 8.07 (d, 1H), 7.27(s, 1H), 3.80-3.78 (m, 1H), 3.58-3.50 (m, 1H), 3.46-3.37 (m, 1H),3.36-3.20 (m, 2H), 2.12-2.03 (m, 1H), 1.83-1.54 (m, 4H), 0.92-0.80 (m,4H); LCMS (APCI+) m/z 318 (M + H)+, Retention time = 1.99 minutes 180

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)propionamide ¹H NMR (400 MHz, D₂O) δ 8.07 (d, 1H), 7.27(s, 1H), 3.88-3.79 (m, 1H), 3.57-3.48 (m, 1H), 3.47-3.39 (m, 1H),3.36-3.27 (m, 2H), 3.27-3.18 (m, 1H), 2.43-2.35 (m, 2H), 2.12-2.01 (m,1H), 1.81-1.68 (m, 1H), 1.68-1.54 (m, 2H), 1.10-1.03 (m, 3H); LCMS(APCI+) m/z 306, 307.1 (M + H)+ Retention time = 1.95 minutes 181

(R)-N-(4-(3-Aminopiperidin-1- yl)-5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxy-2- methylpropanamide ¹H NMR (400 MHz, D₂O) δ8.07 (d, 1H), 7.44 (s, 1H), 3.80-3.73 (m, 1H), 3.52-3.39 (m, 2H),3.33-3.17 (m, 2H), 2.12-2.02 (m, 1H), 1.81-1.50 (m, 3H), 1.37 (m, 6H);LCMS (APCI+) 366.1 (M + H)+, Retention time = 2.06 minutes 182

N-(5-Bromo-4- (hexahydropyrrolo[3,4-b]pyrrol- 5(1H)-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide ¹H NMR (400 MHz, D₂O) δ 9.15 (s, 1H),8.84-8.83 (m, 1H), 8.78-8.75 (m, 1H0, 8.24 (s, 1H), 8.00-7.96 (m, 1H),7.43 (s, 1H), 4.15-4.11 (m, 1H), 3.97-3.92 (m, 1H), 3.73-3.69 (m, 1H),3.65-3.61 (m, 1H), 3.54-3.50 (m, 1H), 3.27-3.23 (m, 2H), 2.90-2.87 (m,1H) 1.96-1.86 (m, 2H); LCMS (APCI+) m/z 427, 429 (M + H)+ 183A

(S)-N-(4-(3-Aminopyrrolidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide ¹H NMR (400 MHz, D₂O) δ 8.15 (s, 1H), 7.25(s, 1H), 4.06-4.01 (m, 1H), 3.96-3.93 (m, 1H), 3.87-3.84 (m, 1H),3.82-3.76 (m, 1H), 3.72-3.67 (m, 1H), 2.62-2.58 (m, 1H), 2.38-2.32 (m,1H), 2.02-2.00 (m, 1H), 1.08-1.06 (d, 6H); LCMS (APCI+) m/z 366, 368(M + H)+ 183B

(R)-N-(4-(3-Aminopyrrolidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)isobutyramide ¹H NMR (400 MHz, D₂O) δ 8.16 (s, 1H), 7.27(s, 1H), 4.00-3.93 (m, 2H), 3.84-3.73 (m, 2H), 3.69-3.60 (m, 1H),2.63-2.56 (m, 1H), 2.83-2.33 (m, 1H), 2.04-2.01 (m, 1H), 1.08-1.06 (d,6H); LCMS (APCI+) m/z 366, 368 (M + H)+ 184

(R)-N-(4-(3-aminopyrrolidin-1- yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2- isopropoxyacetamide ¹H NMR (400 MHz, D₂O) δ 8.17 (s,1H), 7.32 (s, 1H), 4.10 (s, 2H), 3.97-3.95 (m, 2H), 3.81-3.62 (m, 4H),2.37-2.35 (m, 1H), 2.10-2.00 (m, 1H), 1.11-1.10 (d, 6H); LCMS (APCI+)m/z 396, 398 (M + H)+

While the invention has been described in conjunction with theenumerated embodiments, it will be understood that they are not intendedto limit the invention to those embodiments. On the contrary, theinvention is intended to cover all alternatives, modifications andequivalents, which may be included within the scope of the presentinvention as defined by the claims. Thus, the foregoing description isconsidered as illustrative only of the principles of the invention.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

1. (canceled)
 2. A compound of Formula:

or a stereoisomer, tautomer or salt thereof, wherein: each PG isindependently a protecting group selected from t-butyloxycarbonyl (BOC),9-fluorenylmethyleneoxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); Ais selected from a direct bond or CR^(a)R^(b); each R^(1a) isindependently halogen or OH; R^(1c) is C₁-C₆ alkyl, C₃-C₆ cycloalkyl,phenyl or a 5 or 6 membered heteroaryl, wherein the alkyl, cycloalkyl,phenyl or heteroaryl are optionally substituted with one or more groupsselected from halogen, CN, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl) andNR^(c)R^(d); R^(1d) is hydrogen or —S(C₁-C₆ alkyl); R² is selected fromC₁-C₆ alkyl, —O(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl), a saturated or partiallyunsaturated C₃-C₆ cycloalkyl, phenyl, a saturated or partiallyunsaturated 4 to 6 membered heterocyclic, a 5 or 6 membered heteroaryl,an 8 to 10 membered bicyclic aryl, an 8 to 10 membered bicyclicheterocyclic, and an 8 to 10 membered bicyclic heteroaryl, wherein thealkyls, cycloalkyl, phenyl, heterocyclics, heteroaryls and aryl areoptionally substituted with one or more groups selected from OH, CN,halogen, oxo (except not on phenyl, aryl or heteroaryl), CF₃,cyclopropyl, cyclopropylmethyl, —SO₂R^(i), C₁-C₆ alkyl, —O(C₁-C₆ alkyl),—S(C₁-C₆ alkyl), NR^(e)R^(f), and phenyl, wherein the phenyl isoptionally substituted with one or more groups selected from OH, CN,halogen, CF₃, C₁-C₃ alkyl, —O(C₁-C₃ alkyl), and NR^(g)R^(h); R³ isselected from hydrogen and C₁-C₄ alkyl optionally substituted with OH,F, —O(C₁-C₃ alkyl) or C₃-C₆ cycloalkyl; R⁵ is selected from hydrogen andCH₃, or A is CR^(a)R^(b), R^(a) and R^(b) are hydrogen, and R³ and R⁵together with the atoms to which they are attached form a 5 or 6membered ring; R⁶ is selected from hydrogen, F, OH, —OCH₃, C₁-C₃ alkyland cyclopropyl, or A is a direct bond, R^(6a) is hydrogen and R³ and R⁶together with the atoms to which they are attached form a 5 or 6membered ring; R^(6a) is selected from hydrogen, F, OH, and CH₃; R⁷ ishydrogen, or A is CR^(a)R^(b) and R³ and R⁷ together with the atoms towhich they are attached form a 5 or 6 membered ring; R^(a) is hydrogen,or R^(b) is absent and R³ and R^(a) together with the atoms to whichthey are attached form an aromatic 5 or 6 membered ring; R^(b) ishydrogen or absent; R^(c) and R^(d) are independently selected hydrogenand C₁-C₃ alkyl, or R^(c) and R^(d) together with the atom to which theyare attached form a 5 or 6 membered ring; R^(e) and R^(f) areindependently selected hydrogen and C₁-C₃ alkyl; R^(g) and R^(h) areindependently selected from hydrogen and C₁-C₃ alkyl; R^(i) is C₁-C₃alkyl; and p is
 2. 3. The compound of claim 2, wherein R² is selectedfrom C₁-C₆ alkyl, a saturated or partially unsaturated C₃-C₆ cycloalkyl,phenyl, a saturated or partially unsaturated 5 or 6 memberedheterocyclic, a 5 or 6 membered heteroaryl, an 8 to 10 membered bicyclicaryl, an 8 to 10 membered bicyclic heterocyclic, and an 8 to 10 memberedbicyclic heteroaryl, wherein the alkyl, cycloalkyl, phenyl,heterocyclic, heteroaryl and aryl are optionally substituted with one ormore groups selected from OH, CN, halogen, oxo (except not on phenyl,aryl or heteroaryl), CF₃, C₁-C₆ alkyl, —O(C₁-C₆ alkyl), —S(C₁-C₆ alkyl),and NR^(e)R^(f).
 4. The compound of claim 2, wherein R² is selected fromC₁-C₆ alkyl, saturated C₃-C₆ cycloalkyl, phenyl, saturated or partiallyunsaturated 5 or 6 membered heterocyclic, a 5 or 6 membered heteroaryl,and an 8 to 10 membered bicyclic heteroaryl, wherein the alkyl,cycloalkyl, phenyl, heterocyclic and heteroaryl are optionallysubstituted with halogen, oxo (except not on phenyl or heteroaryl), CF₃,C₁-C₆ alkyl, —O(C₁-C₆ alkyl) or C₃-C₆ cycloalkyl.
 5. The compound ofclaim 2, wherein R² is selected from isopropyl, tert-butyl, isobutyl,cyclopropylmethyl, —CH(CH₂CH₃)₂, —CH₂OCH₃, —CH(CH₃)OCH₃, —CH₂CH₂OCH₃,cyclopropyl, cyclobutyl, cyclopentyl, phenyl, 3-methylphenyl,4-fluorophenyl, 3-methoxyphenyl, 3-fluorophenyl,3-chloro-4-fluorophenyl, 3-fluoro-4-methoxyphenyl,3-trifluoromethylphenyl, 2-fluoro-5-methylphenyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, 1-methyl-6-oxo-1,6-dihydropyridin-3-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl, morpholin-2-yl, pyrazol-4-yl,1-methyl-1H-pyrazol-3-yl, 2-methyloxazol-4-yl, 5-methylisoxazol-3-yl,2-methylthiazol-4-yl, pyridin-2-yl, pyridin-3-yl,6-methoxy-pyridin-2-yl, 3-methylpyridin-2-yl, 5-chloro-pyridin-2-yl,5-methylpyridin-2-yl, 2-methylpyridin-3-yl, 5-methylpyridin-3-yl,5-chloropyridin-3-yl, 6-methylpyridin-3-yl, pyrimidin-2-yl,pyrazin-2-yl, 5-methylpyrazin-2-yl and quinoxalin-2-yl.
 6. The compoundof claim 2, wherein R² is selected from methyl, ethyl, propyl,isopropyl, tert-butyl, isobutyl, cyclopropylmethyl, —CH₂CF₃,—CH(CH₂CH₃)₂, —CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH(CH₃)OCH₃, —CH₂CH₂OCH₃,—CH(CH₃)OH, —C(CH₃)₂OH, —CH₂CN, —CH₂CH₂F, —C(CH₃)₂F, —CH(CH₃)CH₂CH₃,—CH₂OCH(CH₃)₂, —CH(CH₃)OCH(CH₃)₂, —CH₂SO₂CH₃, —CH(CH₃)phenyl,—CH₂(phenyl), —OCH₂CH₃, —NH(CH₂CH₃), cyclopropyl, cyclobutyl,cyclopentyl, 1-(trifluoromethyl)cyclopropyl, 1-(methoxy)cyclopropyl,2,2-difluorocyclopropyl, 1-methylcyclopropyl, 2-phenylcyclopropyl,2,2-dimethylcyclopropyl, phenyl, 3-methylphenyl, 4-fluorophenyl,3-methoxyphenyl, 3-fluorophenyl, 3-chloro-4-fluorophenyl,3-fluoro-4-methoxyphenyl, 3-trifluoromethylphenyl,2-fluoro-5-methylphenyl, 3-methyloxetan-3-yl, azetidin-1-yl,tetrahydrofuran-2-yl, tetrahydrofuran-3-yl,1-methyl-6-oxo-1,6-dihydropyridin-3-yl,1-methyl-6-oxo-1,6-dihydropyridazin-3-yl,1-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl,1-(cyclopropylmethyl)-6-oxo-1,6-dihydropyridazin-3-yl, morpholin-2-yl,pyrrolidin-1-yl, 5-oxopyrrolidin-2-yl, pyrazol-4-yl,1-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-4-yl, 2-methyloxazol-4-yl,5-methylisoxazol-3-yl, 2-methylthiazol-4-yl, pyridin-2-yl, pyridin-3-yl,6-methoxy-pyridin-2-yl, 3-methylpyridin-2-yl, 5-chloro-pyridin-2-yl,5-trifluoromethylpyridin-2-yl, 2-methylpyridin-3-yl,5-methylpyridin-3-yl, 5-chloropyridin-3-yl, 6-methylpyridin-3-yl,pyrimidin-2-yl, 5-ethylpyrimidin-2-yl, pyrazin-2-yl,5-methylpyrazin-2-yl, and quinoxalin-2-yl.
 7. The compound of claim 2,wherein A is a direct bond.
 8. The compound of claim 2, wherein A isCR^(a)R^(b).
 9. The compound of claim 2, wherein R³ is selected fromhydrogen or C₁-C₄ alkyl optionally substituted with OH, F or C₃-C₆cycloalkyl.
 10. The compound of claim 2, wherein R³ is selected fromhydrogen, methyl, isopropyl, isobutyl, CH₂CH₂OH and cyclopropylmethyl.11. The compound of claim 2, wherein R³ is selected from hydrogen,methyl, ethyl, isopropyl, isobutyl, CH₂CH₂OH, CH₂CH₂OCH₃, CH₂CH₂F andcyclopropylmethyl.
 12. The compound of claim 2, wherein R⁵ is selectedfrom hydrogen and CH₃.
 13. The compound of claim 2, wherein A isCR^(a)R^(b), R^(a) and R^(b) are hydrogen, and R³ and R⁵ together withthe atoms to which they are attached form a 5 or 6 membered ring. 14.The compound of claim 2, wherein R⁶ is selected from hydrogen, F, OH,—OCH₃ and C₁-C₃ alkyl.
 15. The compound of claim 2, wherein R⁶ ishydrogen.
 16. The compound of claim 2, wherein A is a direct bond,R^(6a) is hydrogen and R³ and R⁶ together with the atoms to which theyare attached form a 5 or 6 membered ring.
 17. The compound of claim 2,wherein R⁶ is selected from hydrogen, F, —OCH₃, methyl and cyclopropyl.18. The compound of claim 2, wherein R⁷ is hydrogen.
 19. The compound ofclaim 2, wherein A is CR^(a)R^(b) and R³ and R⁷ together with the atomsto which they are attached form a 5 or 6 membered ring.
 20. The compoundof claim 2, wherein each R^(1a) is independently halogen.
 21. Thecompound of claim 2, wherein each R^(1a) is independently OH.
 22. Thecompound of claim 2, wherein R^(1c) is selected from C₃-C₆ cycloalkyland C₁-C₆ alkyl, wherein the alkyl is optionally substituted with one ormore F groups.
 23. The compound of claim 2, wherein R^(1c) is selectedfrom cyclopropyl and CF₃.
 24. The compound of claim 2, wherein R^(1c) isselected from methyl, ethyl, isopropyl, cyclopropyl, phenyl and6-methylpyridin-3-yl; and R^(1d) is selected from SCH₃, —SCH₂CH₃, and—SCH(CH₃)₂.